U.S. patent number 11,248,025 [Application Number 16/890,749] was granted by the patent office on 2022-02-15 for il-2alpha receptor subunit binding compounds.
This patent grant is currently assigned to MEDIKINE, INC.. The grantee listed for this patent is MEDIKINE, INC.. Invention is credited to Alice V. Bakker, Ronald W. Barrett, Steven E. Cwirla, William J. Dower, Michael C. Needels.
United States Patent |
11,248,025 |
Dower , et al. |
February 15, 2022 |
IL-2alpha receptor subunit binding compounds
Abstract
Peptidyl IL-2R.alpha. ligands and compounds comprising the
IL-2R.alpha. ligands are disclosed. The IL-2R.alpha. ligands and
compounds such as synthetic monomers, homodimers, or heteromers and
recombinant fusion proteins comprising the IL-2R.alpha. ligands can
be used as targeting or imaging agents, as diagnostics or to treat
cancers and autoimmune diseases.
Inventors: |
Dower; William J. (Menlo Park,
CA), Needels; Michael C. (Menlo Park, CA), Barrett;
Ronald W. (Menlo Park, CA), Bakker; Alice V. (Menlo
Park, CA), Cwirla; Steven E. (Menlo Park, CA) |
Applicant: |
Name |
City |
State |
Country |
Type |
MEDIKINE, INC. |
Menlo Park |
CA |
US |
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Assignee: |
MEDIKINE, INC. (Menlo Park,
CA)
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Family
ID: |
1000006118668 |
Appl.
No.: |
16/890,749 |
Filed: |
June 2, 2020 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20200399314 A1 |
Dec 24, 2020 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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62856305 |
Jun 3, 2019 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07K
7/08 (20130101); A61K 38/00 (20130101) |
Current International
Class: |
C07K
7/08 (20060101); A61K 38/00 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Morrison, Combinatorial alanine-scanning, Current Opinion in
Chemical Biology 2001, 5:302-307 (Year: 2001). cited by examiner
.
Partial Search for Application No. PCT/US2020/035747, dated Oct. 5,
2020, 18 pages. cited by applicant .
International Search Report and Written Opinion for Application No.
PCT/US2020/035747, dated Dec. 1, 2020, 22 pages. cited by applicant
.
Gronwall et al., "Generation of Affibody ligands binding
interleukin-2 receptor .alpha./CD25", Biotechnology and Applied
Biochemistry, 2008, vol. 50, p. 97-112. cited by applicant .
Malek, T., "The Biology of Interleukin-2", Annual Review of
Immunology, Annual Reviews Inc., 2008, vol. 26, p. 453-479. cited
by applicant .
Uniprot Database, Accession No. A0A3P7JJB2, Feb. 13, 2019, 1 page.
cited by applicant.
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Primary Examiner: Heard; Thomas S
Parent Case Text
This application claims the benefit under 35 U.S.C. .sctn. 119(e)
of U.S. Provisional Application No. 62/856,305 filed on Jun. 3,
2019, which is incorporated by reference in its entirety.
Claims
What is claimed is:
1. An IL-2R.alpha. ligand, wherein, the IL-2R.alpha. ligand binds
to the human IL-2R.alpha. subunit with an IC.sub.50 of less than
100 .mu.M; and the IL-2R.alpha. ligand comprises an amino acid
sequence selected from any one of SEQ ID NOS: 4, 9, 24, 31, 44, 50,
67, 79, 100, 112, 135, 144, 154, 172, 180, 203, 210, 219, 234, 250,
and 418: TABLE-US-00046 SEQ ID NO: 4 F L H W P V Y F C Q V M SEQ ID
NO: 9 F I P W D E Y F K Q V L SEQ ID NO: 24 F V H C T L L G C W S G
SEQ ID NO: 31 W V I C S A V G C R P F SEQ ID NO: 44 H V I C S V N G
G C R G SEQ ID NO: 50 E Q F C L V S D P M A C W S L SEQ ID NO: 67 R
R F C L R S E P A A C W F V SEQ ID NO: 79 S K C V Y D Y N F G T C I
F SEQ ID NO: 100 S L N C K T R P G L R W C T W T SEQ ID NO: 112 A W
E C L F L P G H R G C S L F SEQ ID NO: 135 R Q F C L V S P G Y E D
C W F V SEQ ID NO: 144 S A C Q L K W D E G W T C L F SEQ ID NO: 154
R G C S L V W S G S W E C I F SEQ ID NO: 172 G C T L S W N Q G W W
H C V SEQ ID NO: 180 A R C S L H H T G S R Y E C I F SEQ ID NO: 203
T C R L K R S G P N S W E C I SEQ ID NO: 210 V R C R L A R P G L T
W E C L S SEQ ID NO: 219 Q L C P W S D P G S W G P C P L SEQ ID NO:
234 G C Q L V W Q D D S Y M C F Y SEQ ID NO: 250 W C I G Q P L F R
Q G S C K SEQ ID NO: 418 F V P W D V Y F S Q I L G G.
2. The IL-2R.alpha. ligand of claim 1, wherein the IL-2R.alpha.
ligand comprises the amino acid sequence of SEQ ID NO: 4.
3. The IL-2R.alpha. ligand of claim 1, wherein the IL-2R.alpha.
ligand comprises the amino acid sequence of SEQ ID NO: 9.
4. The IL-2R.alpha. ligand of claim 1, wherein the IL-2R.alpha.
ligand comprises the amino acid sequence of SEQ ID NO: 24.
5. The IL-2R.alpha. ligand of claim 1, wherein the IL-2R.alpha.
ligand comprises the amino acid sequence of SEQ ID NO: 31.
6. The IL-2R.alpha. ligand of claim 1, wherein the IL-2R.alpha.
ligand comprises the amino acid sequence of SEQ ID NO: 44.
7. The IL-2R.alpha. ligand of claim 1, wherein the IL-2R.alpha.
ligand comprises the amino acid sequence of SEQ ID NO: 50.
8. The IL-2R.alpha. ligand of claim 1, wherein the IL-2R.alpha.
ligand comprises the amino acid sequence of SEQ ID NO: 67.
9. The IL-2R.alpha. ligand of claim 1, wherein the IL-2R.alpha.
ligand comprises the amino acid sequence of SEQ ID NO: 79.
10. The IL-2R.alpha. ligand of claim 1, wherein the IL-2R.alpha.
ligand comprises the amino acid sequence of SEQ ID NO: 100.
11. The IL-2R.alpha. ligand of claim 1, wherein the IL-2R.alpha.
ligand comprises the amino acid sequence of SEQ ID NO: 112.
12. The IL-2R.alpha. ligand of claim 1, wherein the IL-2R.alpha.
ligand comprises the amino acid sequence of SEQ ID NO: 135.
13. The IL-2R.alpha. ligand of claim 1, wherein the IL-2R.alpha.
ligand comprises the amino acid sequence of SEQ ID NO: 144.
14. The IL-2R.alpha. ligand of claim 1, wherein the IL-2R.alpha.
ligand comprises the amino acid sequence of SEQ ID NO: 154.
15. The IL-2R.alpha. ligand of claim 1, wherein the IL-2R.alpha.
ligand comprises the amino acid sequence of SEQ ID NO: 172.
16. The IL-2R.alpha. ligand of claim 1, wherein the IL-2R.alpha.
ligand comprises the amino acid sequence of SEQ ID NO: 180.
17. The IL-2R.alpha. ligand of claim 1, wherein the IL-2R.alpha.
ligand comprises the amino acid sequence of SEQ ID NO: 203.
18. The IL-2R.alpha. ligand of claim 1, wherein the IL-2R.alpha.
ligand comprises the amino acid sequence of SEQ ID NO: 210.
19. The IL-2R.alpha. ligand of claim 1, wherein the IL-2R.alpha.
ligand comprises the amino acid sequence of SEQ ID NO: 219.
20. The IL-2R.alpha. ligand of claim 1, wherein the IL-2R.alpha.
ligand comprises the amino acid sequence of SEQ ID NO: 234.
21. The IL-2R.alpha. ligand of claim 1, wherein the IL-2R.alpha.
ligand comprises the amino acid sequence of SEQ ID. NO: 250.
22. The IL-2R.alpha. ligand of claim 1, wherein the IL-2R.alpha.
ligand comprises the amino acid sequence of SEQ ID. NO: 418.
23. A compound comprising at least one IL-2R.alpha. ligand of claim
1.
24. The compound of claim 23, wherein the compound is selected from
a peptide, a conjugate, and a fusion protein.
25. A pharmaceutical composition comprising the IL-2R.alpha. ligand
of claim 1.
26. A pharmaceutical composition comprising the compound of claim
23.
Description
FIELD
The present disclosure relates to peptidyl IL-2R.alpha. ligands and
to compounds having a peptidyl IL-2R.alpha. ligand. Compounds such
as synthetic monomers, homodimers, heteromers, and recombinant
fusion proteins comprising the IL-2R.alpha. ligands can be used as
targeting agents, imaging agents, diagnostic agents, and as
therapeutics to treat cancer and autoimmune diseases.
SEQUENCE LISTING
The Sequence Listing associated with this application is filed in
electronic format via EFS-Web and is incorporated by reference in
its entirety. Said ASCII copy, created on Jul. 28, 2020, is named
62AJ-000210US-309981_SL.txt and is 200,417 bytes in size.
BACKGROUND
Interleukin-2 (IL-2) plays a crucial role in regulating immune
responses and maintaining peripheral self-tolerance by having both
immuno-stimulatory and immuno-regulatory functions. IL-2 acts
primarily as a T cell growth factor and is essential for the
proliferation and survival of T cells as well as the generation of
effector and memory T cells. IL-2 is a four .alpha.-helical bundle
cytokine that belongs to a family of structurally related cytokines
that includes IL-4, IL-7, IL-9, IL-15, and IL-21. IL-2 is produced
by activated CD4.sup.+ T cells in response to antigen stimulation
and can also be produced by CD8.sup.+ T cells and innate immune
cells such as activated dendritic cells (DCs) and natural killer
(NK) cells.
IL-2 binds to various forms of the IL-2 receptor (IL-2R), notably
the monomeric, dimeric, and trimeric forms. Monomeric IL-2R
consists of the membrane-associated IL-2R.alpha. (CD25) chain,
which also exists in a soluble form; however, it is not capable of
inducing signaling events. The trimeric IL-2R consists of
IL-2R.alpha., IL2-R.beta. (CD122), and IL-2R.gamma., also known as
the common .gamma.-chain (.gamma.c) or CD132 and is shared by all
members of the IL-2 cytokine family. Dimeric IL-2R comprises the
IL-2R.gamma.c and IL-2R.beta. subunits. In contrast to monomeric
IL-2R, both the dimeric and trimeric IL-2 receptors lead to a
downstream signaling cascade upon IL-2 binding. IL-2 binds with
high affinity to the trimeric IL-2R but with low-moderate affinity
to the dimeric IL-2R, varying the sensitivity of the cell to IL-2.
Additionally, IL-2 can bind to IL-2R.alpha. expressed on the
surface of activated dendritic cells for trans presentation to
neighboring cells including antigen-specific naive T cells and NK
cells that express both IL-2R.beta. and IL-2R.gamma.c subunits.
This trans presentation of IL-2 has been shown to facilitate
initial high affinity IL-2 signaling, required early in the immune
response to prime naive T-cells to produce IL-2.
TL-2 is first captured by IL-2R.alpha., bringing about a
conformational change to IL-2, increasing its affinity for
IL-2R.beta.. Association of IL-2 with the IL-2R.alpha..gamma.c
subunits induces the dimerization of the signaling motifs in the
cytoplasmic tails of IL-2R.beta. and IL-2R.gamma.c leading to the
phosphorylation/activation of the Janus kinases, JAK1 and JAK3,
which in turn exert kinase activity on key tyrosine residues in the
tail of the IL-2R.beta. subunit.
Downstream signaling occurs via three major pathways, the JAK-STAT
pathway, the phosphoinositide 3-kinase (PI3K)-AKT pathway, and the
mitogen-activated protein kinase (MAPK) pathway. These pathways
ultimately result in the transcription of target genes that
contribute to IL-2-dependent biological actions, through the
recruitment of the adaptor protein She and the transcription factor
STAT5. Target genes of TL-2 signaling include cyclin D2, bcl-2,
fasL, cd25 (encoding IL-2R.alpha.), socs1-2, and the IL-2 silencing
gene prdm1, which encodes for the transcription factor, BLIMP. The
production of the negative regulator of IL-2 BLIMP1 is essential
for maintaining the balance between effector T cells and Treg
cells, which is crucial for immune homeostasis.
IL-2 plays a dual role in T cell activation by stimulating the
proliferation and differentiation or T cells as well as by
maintaining and expanding the population of immuno-suppressive Treg
cells. The conventional naive CD4+ and CD8+ T cells express the
dimeric TL-2R, and therefore require a high concentration of IL-2
to induce their initial proliferation. Once activated, these T
cells express the high-affinity trimeric IL-2R, driving the
differentiation of the cells into either effector (Teff) or memory
cells. This differentiation depends on the strength and duration of
the IL-2 signal.
During the primary expansion of CD8.sup.+ T cells due to
low-moderate levels of IL-2, a subset of CD8.sup.+ T cells will
differentiate into memory T cells. They do this by downregulating
CD25 and upregulating CD127 (IL-7R) and CD62 (L-selectin), which
are crucial receptors for secondary responses upon re-infection.
During an acute infection, sustained high levels of IL-2 leads to a
rapid up-regulation of CD25, and the differentiation of CD8+ cells
into cytotoxic effector cells. The upregulation induces an IL-2
driven expression of the death receptor fas and fasL, causing
activation-induced cell death (AICD) upon pathogen clearance. For
CD4.sup.+ T cells, the activation of STAT5 signaling by IL-2
influences their differentiation into multiple helper T cell
populations, including Th1, Th2, and Th17 by regulating the
expression of the appropriate receptors for each response.
Homeostatic or background levels of IL-2 are essential for the
survival and function of Treg cells by maintaining the expression
of FOXP3 and CD25. Treg cells naturally occur in the thymus and
upon contact with self-peptides become activated. Additionally,
Treg cells can be generated by stimulation of conventional
CD4.sup.+ T cells upon interaction with antigens in peripheral
lymphoid organs. Because Treg cells do not produce IL-2, Treg cells
are dependent on IL-2 producing cells such as conventional T cells.
Additionally, due to the high expression of IL-2R.alpha. (CD25)
Treg cells are able to consume and limit the systemic concentration
of IL-2, ensuring the regulation of the immune balance. In the
absence of IL-2, the number of Treg cells decreases and the number
of effector T cells increases, leading to an enhanced
susceptibility to autoimmune and inflammatory disorders. Therefore,
the unique activation of Treg cells at low levels of IL-2, which
does not activate CD4.sup.+ or CD8.sup.+ T cells, has allowed for
the development of IL-2 as a therapeutic in autoimmune and
inflammatory diseases.
The production of IL-2 from both arms of the immune system
highlights the importance of IL-2 in the early stages of infection,
as well as the secondary adaptive response. Furthermore, the dual
functions of IL-2 in both protective immunity and in immune
tolerance allows IL-2 to be a potential therapeutic as both an
immune stimulant for cancer treatment and as an immune suppressor
for the treatment of autoimmune disease.
SUMMARY
According to the present invention, IL-2R.alpha. ligands bind to
the human IL-2R.alpha. subunit with an IC.sub.50 of less than 100
.mu.M.
According to the present invention, compounds comprise an
IL-2R.alpha. ligand according to the present invention.
According to the present invention, pharmaceutical compositions
comprise an IL-2R.alpha. ligand according to the present invention;
a compound according to the present invention; or a combination of
any of the foregoing.
According to the present invention, methods of treating cancer in a
patient, comprise administering to a patient in need of such
treatment a therapeutically effective amount of a pharmaceutical
composition according to the present invention.
According to the present invention, methods of treating an
autoimmune disease in a patient, comprise administering to a
patient in need of such treatment, a therapeutically effective
amount of a pharmaceutical composition according to the present
invention.
According to the present invention, methods of screening compounds
for IL-2.alpha. activity, comprise contacting a cell with an
IL-2R.alpha. ligand according to the present invention; the
compound according to the present invention; or a combination of
any of any of the foregoing wherein the cell expresses an
IL-2.alpha. subunit; and contacting the cell with a test compound;
and determining the activity of the test compound.
According to the present invention, methods of treating a disease
in a patient, wherein the IL-2 receptor signaling pathway is
associated with the etiology of the disease, comprise administering
to a patient in need of such treatment a therapeutically effective
amount of a compound comprising an IL-2R.alpha. ligand according to
the present invention, or a pharmaceutical composition thereof.
According to the present invention, methods of treating a disease
in a patient, wherein activating the IL-2 receptor is effective in
treating the disease, comprise administering to a patient in need
of such treatment a therapeutically effective amount of a compound
comprising an IL-2R.alpha. ligand according to the present
invention or a pharmaceutical composition thereof.
According to the present invention, methods of treating a disease
in a patient, wherein inhibiting the IL-2 receptor is effective in
treating the disease, comprise administering to a patient in need
of such treatment a therapeutically effective amount of a compound
comprising an IL-2R.alpha. ligand according to the present
invention or a pharmaceutical composition thereof.
According to the present invention, methods of treating a disease
in a patient, wherein modulating the activity of the IL-2R.alpha.
subunit is effective in treating the disease, comprise
administering to a patient in need of such treatment a
therapeutically effective amount of a compound comprising an
IL-2R.alpha. ligand according to the present invention or a
pharmaceutical composition thereof.
According to the present invention, methods of treating a disease
in a patient, wherein inhibiting binding to the IL-2R.alpha.
subunit is effective in treating the disease, comprise
administering to a patient in need of such treatment a
therapeutically effective amount of a compound comprising an
IL-2R.alpha. ligand according to the present invention or a
pharmaceutical composition thereof.
According to the present invention, methods of treating a disease
in a patient, wherein the etiology of the disease is associated
with activation of Treg cells, comprise administering to a patient
in need of such treatment a therapeutically effective amount of a
compound comprising an IL-2R.alpha. ligand according to the present
invention or a pharmaceutical composition thereof.
According to the present invention, methods of treating a disease
in a patient, wherein the etiology of the disease is associated
with cells exhibiting a high IL-2R.alpha. expression, comprise
administering to a patient in need of such treatment a
therapeutically effective amount of a compound comprising an
IL-2R.alpha. ligand according to the present invention or a
pharmaceutical composition thereof.
According to the present invention, methods of imaging cells
expressing the IL-2R.alpha. subunit comprise administering to a
patient an effective amount of a compound comprising an
IL-2R.alpha. ligand according to the present invention.
According to the present invention, methods of diagnosing a disease
in a patient wherein the disease is associated with cells
expressing the IL-2R.alpha. subunit comprise administering to a
patient an effective amount of a compound comprising an
IL-2R.alpha. ligand according to the present invention.
According to the present invention, methods of targeting a compound
to cells expressing the IL-2R.alpha. subunit comprise administering
to a patient an effective amount of a compound comprising an
IL-2R.alpha. ligand according to the present invention.
According to the present invention, methods of delivering a
cytotoxic compound to cells expressing the IL-2R.alpha. subunit
comprise administering to a patient an effective amount of a
compound comprising a cytotoxic moiety and an IL-2R.alpha. ligand
according to the present invention.
DETAILED DESCRIPTION
A dash ("-") that is not between two letters or symbols is used to
indicate a point of attachment for a moiety or substituent. For
example, --X.sup.1--X.sup.2-- denotes amino acids X.sup.1 and
X.sup.2 covalently bonded through a single bond.
"Affinity" refers to strength of the binding interaction between a
single biomolecule to its ligand/binding partner. Affinity is
expressed as the IC.sub.50.
"Agonist" refers to a biologically active ligand or compound that
binds to its complementary biologically active receptor or subunit
and activates the receptor to cause a biological response mediated
by the receptor, or to enhance a preexisting biological activity
mediated by the receptor.
"Partial agonist" refers to a compound that provides a level of
activation, that is, for example, less than 75% of maximum
activation, less than 50%, less than 25%, less than 10%, or less
than 1% of the maximum activation. A partial IL-2R agonist exhibits
a level of activation that is less than the level of activation
provided by IL-2.
"Antagonist" refers to a biologically active ligand or compound
that binds to its complementary receptor or subunit and blocks or
reduces a biological response of the receptor.
Amino acid residues are abbreviated as follows: alanine is Ala or
A; arginine is Arg is R; asparagine is Asn or N; aspartic acid is
Asp or D; cysteine is Cys or C; glutamic acid is Glu or E;
glutamine is Gln or Q; glycine is Gly or G; histidine is His or H;
isoleucine is Ile or I; leucine is Leu or L; lysine is Lys or K;
methionine is Met or M; phenylalanine is Phe or F; proline is Pro
or P; serine is Ser or S; threonine is Thr or T; tryptophan is Trp
or W; tyrosine is Tyr or Y; and valine is Val or V.
"Non-natural amino acids" include, for example, .beta.-amino acids,
homo-amino acids, proline and pyruvic acid derivatives, histidine
derivatives with alkyl or heteroatom moieties attached to the
imidazole ring, amino acids with pyridine-containing side chains,
3-substituted alanine derivatives, glycine derivatives,
ring-substituted phenylalanine and tyrosine derivatives, and
N-methyl amino acids.
Amino acids having a large hydrophobic side chain include
isoleucine (I), leucine (L), methionine (M), valine (V),
phenylalanine (F), tyrosine (Y), and tryptophan (W).
Amino acids having a small hydrophobic side chain include alanine
(A), glycine (G), proline (P), serine (S), and threonine (T).
Amino acids having a basic side chain include arginine (R), lysine
(K), and histidine (H).
Amino acids having an acidic side chain include aspartate (D) and
glutamate (E).
Amino acids having a polar/neutral side chain include histidine
(H), asparagine (N), glutamine (Q), serine (S), threonine (T), and
tyrosine (Y).
Amino acids having an aromatic side chain include phenylalanine
(F), histidine (H), tryptophan (W), and tyrosine (Y).
Amino acids having a hydroxyl side chain include serine (S),
threonine (T), or tyrosine (Y).
"Conservative amino acid substitution" means that amino acids
within each of the following groups can be substituted with another
amino acid within the group: amino acids having a small hydrophobic
side chain comprising alanine (A), glycine (G), proline (P), serine
(S), and threonine (T); amino acids having a hydroxyl-containing
side chain comprising serine (S), threonine (T), and tyrosine (Y);
amino acids having an acidic side chain comprising aspartate (D)
and glutamate (E); amino acids comprising a polar-neutral side
chain comprising histidine (H), asparagine (N), glutamine (Q),
serine (S), threonine (T), and tyrosine (Y); amino acids having a
basic side chain comprising arginine (R), lysine (K), and histidine
(H); amino acids having a large hydrophobic side chain comprising
isoleucine (I), leucine (L), methionine (M), valine (V),
phenylalanine (F), tyrosine (Y), and tryptophan (W); and amino
acids having an aromatic side chain comprising phenylalanine (F),
histidine (H), tryptophan (W), and tyrosine (Y).
"Expression" as used herein generally refers to expression of
construct such as an IL-2 receptor or the outer surface of a
cell.
Molecular weight refers to the number average molecular weight as
determined by gel permeation chromatography using a polystyrene
standard.
A linker refers to a moiety that binds at least one IL-2R ligand
such as an IL-2R.alpha. ligand, an IL-2R.beta. ligand, and/or an
IL-2R.gamma.c ligand. A linker can bind to another IL-2R ligand
which can be the same IL-2R ligand or a different IL-2R ligand. A
linker can also bind to one or more additional moieties and/or
compounds that can provide a desired physiological function. A
linker can be divalent or multivalent. A linker can be
hydrolytically stable or may be cleavable such as a physiologically
hydrolyzable or enzymatically degradable linkage. A linker can bind
IL-2R ligands to form dimers, trimers, or higher order multi-ligand
peptides (heteromers) and compounds.
A "physiologically cleavable" or "hydrolyzable" or "degradable"
bond refers to a bond that reacts with water (i.e., is hydrolyzed)
under physiological conditions. The tendency of a bond to hydrolyze
in water will depend not only on the general type of linkage
connecting two central atoms but also on the substituents attached
to these central atoms. Suitable hydrolytically unstable or weak
linkages include but are not limited to carboxylate ester,
phosphate ester, anhydrides, acetals, ketals, acyloxyalkyl ether,
imines, orthoesters, peptides and oligonucleotides.
An "enzymatically degradable linkage" refers to a linkage that can
be degraded or cleaved by one or more enzymes.
A "hydrolytically stable" linkage or bond refers to a chemical
bond, such as a covalent bond, that is substantially stable in
water such that the chemical bond does not undergo hydrolysis under
physiological conditions to any appreciable extent over an extended
period of time. Examples of hydrolytically stable linkages include,
for example, carbon-carbon bonds (e.g., in aliphatic chains),
ethers, amides, urethanes, and the like. Generally, a
hydrolytically stable linkage is one that exhibits a rate of
hydrolysis of less than about 1% to 2% per day under physiological
conditions.
An "IL-2R.beta. ligand" refers to a peptide capable of binding to
the IL-2R.beta. subunit of a mammalian IL-2 receptor, such as a
human IL-2 receptor, with an affinity (IC.sub.50) less than 100
.mu.M. Suitable IL-2R.beta. ligands are disclosed, for example, in
U.S. Application Publication No. 2020/0040034 A1 and in U.S.
Provisional Application No. 62/930,758 filed on Nov. 5, 2019, each
of which is incorporated by reference in its entirety.
An "IL-2R.gamma.c ligand" refers to a peptide capable of binding to
the IL-2R.gamma.c subunit of a mammalian IL-2 receptor, such as a
human IL-2 receptor, with an affinity (IC.sub.50) less than 100
.mu.M. IL-2R.gamma.c ligands are disclosed in U.S. Application
Publication No. 2020/0040036 A1 and in U.S. Provisional Application
No. 62/930,758 filed on Nov. 5, 2019, each of which is incorporated
by reference in its entirety.
An "IL-2R.alpha. ligand" refers to a peptide capable of binding to
the IL-2R.alpha. subunit of a mammalian IL-2 receptor, such as a
human IL-2 receptor, with an affinity (IC.sub.50) less than 100
.mu.M.
The "human IL-2R.beta. ligand" refers to a peptide capable of
binding to the IL-2R.beta. subunit of the human IL-2 receptor with
an affinity less than 100 .mu.M.
The "human IL-2R.gamma.c ligand" refers to a peptide capable of
binding to the IL-2R.gamma.c subunit of a mammalian IL-2 receptor
with an affinity (IC.sub.50) less than 100 .mu.M.
The "human IL-2R.alpha. ligand" comprises refers to a peptide
capable of binding to the IL-2R.alpha. subunit of the human IL-2
receptor with an affinity (IC.sub.50) less than 100 .mu.M.
The "human IL-2R.beta. subunit" refers to NP_000869.1.
The "human IL-2R.gamma.c subunit" refers to NP_000197.1.
The "human IL-2R.alpha. subunit" refers to NP_001295172.1 and/or
NP_001295171.1,
An "IL-2R binding fusion protein" refers to a protein made by
recombinant DNA technology in which the translational reading frame
of an IL-2R ligand is fused to that of another protein ("IL-2R
binding fusion partner") to produce a single recombinant
polypeptide. An IL-2R fusion protein can comprise an IL-2R.alpha.
ligand, an IL-2R.beta. ligand, and/or an IL-2R.gamma.c ligand. An
IL-2R binding fusion protein can be produced as a disulfide-linked
dimer, joined together by disulfide bonds located in the hinge
region. An IL-2R ligand binding fusion protein can include a
peptide linker such as an amino acid sequence located between two
proteins comprising a fusion protein, such that the linker peptide
sequence is not derived from either partner protein. Peptide
linkers can be incorporated into fusion proteins as spacers to
promote proper protein folding and stability of the component
protein moieties, to improve protein expression, or to enable
better bioactivity of the two fusion partners.
Bioisosteres are atoms or molecules that fit the broadest
definition for isosteres and is used interchangeably with the term
isostere. The concept of bioisosterism is based on the concept that
single atom, groups, moieties, or whole molecules, which have
chemical and physical similarities produce similar biological
effects. A bioisostere of a parent compound can still be recognized
and accepted by its appropriate target, but its functions will be
altered as compared to the parent molecule. Parameters affected
with bioisosteric replacements include, for example, size,
conformation, inductive and mesomeric effects, polarizability,
capacity for electrostatic interactions, charge distribution,
H-bond formation capacity, pKa (acidity), solubility,
hydrophobicity, lipophilicity, hydrophilicity, polarity, potency,
selectivity, reactivity, or chemical and metabolic stability, ADME
(absorption, distribution, metabolism, and excretion). Although
common in pharmaceuticals, carboxyl groups or carboxylic acid
functional groups (--CO.sub.2H) in a parent molecule may be
replaced with a suitable surrogate or (bio)isostere to overcome
chemical or biological shortcomings while retaining the desired
attributes of the parent molecule bearing one or more carboxyl
groups or carboxylic acid functional groups (--CO.sub.2H).
"Isostere" or "isostere replacement" refers to any amino acid or
other analog moiety having physiochemical and/or structural
properties similar to a specified amino acid. An "isostere" or
"suitable isostere" of an amino acid is another amino acid of the
same class, wherein amino acids belong to the following classes
based on the propensity of the side chain to be in contact with
polar solvent like water: hydrophobic (low propensity to be in
contact with water), polar or charged (energetically favorable
contact with water). Examples of charged amino acid residues
include lysine (+), arginine (+), aspartate (-) and glutamate (-).
Examples of polar amino acids include serine, threonine,
asparagine, glutamine, histidine and tyrosine. Illustrative
hydrophobic amino acids include alanine, valine, leucine,
isoleucine, proline, phenylalanine, tryptophan, cysteine and
methionine. The amino acid glycine does not have a side chain and
is hard to assign to one of the above classes. However, glycine is
often found at the surface of proteins, often within loops,
providing high flexibility to these regions, and an isostere may
have a similar feature. Proline has the opposite effect, providing
rigidity to the protein structure by imposing certain torsion
angles on the segment of the polypeptide chain. An isostere can be
a derivative of an amino acid, e.g., a derivative having one or
more modified side chains as compared to the reference amino
acid.
"Cyclized" refers to a reaction in which one part of a peptide or
polypeptide molecule becomes linked to another part of the peptide
or polypeptide molecule to form a closed ring, such as by forming a
disulfide bridge or other similar bond, e.g., a lactam bond. A
peptide monomer compound or monomer subunit of peptide dimer
compounds can be cyclized via an intramolecular bond between two
amino acid residues present in the peptide monomer or monomer
subunit.
"Patient" refers to a mammal, for example, a human.
"Peptide" refers to a polymer in which the monomers are
.alpha.-amino acids joined together through amide bonds. A peptide
can comprise less than 100 amino acids, less than 50 amino acids,
less than 40 amino acids, less than 30 amino acids, or less than 20
amino acids. A peptide can comprise naturally-occurring
.alpha.-amino acids, non-naturally occurring amino acids, or a
combination thereof.
"Polypeptide" refers to a polymer in which the monomers are
.alpha.-amino acids joined together through amide bonds and
comprise greater than 50 amino acids.
"N-terminus" refers to the end of a peptide or polypeptide, such as
an N-terminus of a peptide or polypeptide comprising an
IL-2R.alpha. ligand, an IL-2R.beta. ligand, and/or an IL-2R.gamma.c
ligand, that bears an amino group in contrast to the carboxyl end
bearing a carboxyl acid group.
"C-terminus" refers to the end of a peptide or polypeptide, such as
a C-terminus of a peptide or polypeptide comprising an IL-2R.alpha.
ligand, an IL-2R.beta. ligand, and/or an IL-2R.gamma.c ligand, that
bears a carboxylic acid group in contrast to the amino terminus
bearing an amino group.
"Pharmaceutically acceptable" refers to approved or approvable by a
regulatory agency of the Federal or a state government or listed in
the U.S. Pharmacopoeia or other generally recognized pharmacopoeia
for use in animals, and more particularly in humans.
"Pharmaceutically acceptable salt" refers to a salt of a compound,
which possesses the desired pharmacological activity of the parent
compound. Such salts include acid addition salts, formed with
inorganic acids and one or more protonable functional groups such
as primary, secondary, or tertiary amines within the parent
compound. Examples of inorganic acids include hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and
the like. Salts can be formed with organic acids such as acetic
acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,
glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic
acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric
acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic
acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,
1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,
benzenesulfonic acid, 4-chlorobenzenesulfonic acid,
2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic
acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid,
glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid,
tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid,
glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid,
muconic acid, and the like. A salt can be formed when one or more
acidic protons present in the parent compound are replaced by a
metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an
aluminum ion, or combinations thereof; or coordinates with an
organic base such as ethanolamine, diethanolamine, triethanolamine,
and N-methylglucamine. A pharmaceutically acceptable salt can be
the hydrochloride salt. A pharmaceutically acceptable salt can be
the sodium salt. A compound can have two or more ionizable groups,
a pharmaceutically acceptable salt comprises one or more
counterions, such as a bi-salt, for example, a dihydrochloride
salt.
"Pharmaceutically acceptable salt" includes hydrates and other
solvates, as well as salts in crystalline or non-crystalline form.
Where a particular pharmaceutically acceptable salt is disclosed,
it is understood that the particular salt (e.g., a hydrochloride
salt) is an example of a salt, and that other salts may be formed
using techniques known to one of skill in the art. Additionally,
one of skill in the art would be able to convert the
pharmaceutically acceptable salt to the corresponding compound,
free base and/or free acid, using techniques generally known in the
art.
"Pharmaceutically acceptable vehicle" refers to a pharmaceutically
acceptable diluent, a pharmaceutically acceptable adjuvant, a
pharmaceutically acceptable excipient, a pharmaceutically
acceptable carrier, or a combination of any of the foregoing with
which a compound provided by the present disclosure may be
administered to a patient and which does not destroy the
pharmacological activity thereof and which is non-toxic when
administered in doses sufficient to provide a therapeutically
effective amount of the compound.
"Solvate" refers to a molecular complex of a compound with one or
more solvent molecules in a stoichiometric or non-stoichiometric
amount. Such solvent molecules are those commonly used in the
pharmaceutical arts, which are known to be innocuous to a patient,
e.g., water, ethanol, and the like. A molecular complex of a
compound or moiety of a compound and a solvent can be stabilized by
non-covalent intra-molecular forces such as, for example,
electrostatic forces, van der Waals forces, or hydrogen bonds. The
term "hydrate" refers to a solvate in which the one or more solvent
molecules is water.
"Pharmaceutical composition" refers to a compound comprising an
IL-2R.alpha. ligand provided by the present disclosure or a
pharmaceutically acceptable salt thereof and at least one
pharmaceutically acceptable vehicle, with which the compound or
pharmaceutically acceptable salt thereof is administered to a
patient. Pharmaceutically acceptable vehicles are known in the
art.
"Disease" refers to a disease, disorder, condition, or symptom of
any of the foregoing.
"Preventing" or "prevention" refers to a reduction in risk of
acquiring a disease or disorder (i.e., causing at least one of the
clinical symptoms of the disease not to develop in a patient that
may be exposed to or predisposed to the disease but does not yet
experience or display symptoms of the disease). In some
embodiments, "preventing" or "prevention" refers to reducing
symptoms of the disease by taking the compound in a preventative
fashion. The application of a therapeutic for preventing or
prevention of a disease of disorder is known as prophylaxis.
"Prodrug" refers to a derivative of a therapeutic compound that
requires a transformation within the body to release the active
therapeutic compound. Prodrugs are frequently, although not
necessarily, pharmacologically inactive until converted to the
parent drug.
"Promoiety" refers to a group bonded to a therapeutic compound,
typically to a functional group of the therapeutic compound, via
bond(s) that are cleavable under specified conditions of use. The
bond(s) between the drug and promoiety may be cleaved by enzymatic
or non-enzymatic means. Under the conditions of use, for example
following administration to a patient, the bond(s) between the
therapeutic compound and the promoiety may be cleaved to release
the parent therapeutic compound. The cleavage of the promoiety may
proceed spontaneously, such as via a hydrolysis reaction, or it may
be catalyzed or induced by another agent, such as by an enzyme, by
light, by acid, or by a change of or exposure to a physical or
environmental parameter, such as a change of temperature or pH. The
agent may be endogenous to the conditions of use, such as an enzyme
present in the systemic circulation of a patient to which the
prodrug is administered or the acidic conditions of the stomach or
the agent may be supplied exogenously.
"Substantially" means, for example, greater than 90%, greater than
95%, greater than 98%, or greater than 99%.
"Therapeutically effective amount" refers to the amount of a
compound that, when administered to a patient for treating a
disease, or at least one of the clinical symptoms of a disease, is
sufficient to affect such treatment of the disease or symptom
thereof. A "therapeutically effective amount" may vary depending,
for example, on the compound, the disease and/or symptoms of the
disease, the severity of the disease and/or symptoms of the disease
or disorder, the age, weight, and/or health of the patient to be
treated, and the judgment of the prescribing physician. A
therapeutically effective amount in any given instance may be
ascertained by those skilled in the art or capable of determination
by routine experimentation.
"Therapeutically effective dose" refers to a dose that provides
effective treatment of a disease or disorder in a patient. A
therapeutically effective dose may vary from compound to compound,
and from patient to patient, and may depend upon factors such as
the condition of the patient and the route of delivery. A
therapeutically effective dose may be determined in accordance with
routine pharmacological procedures known to those skilled in the
art.
"Treating" or "treatment" of a disease refers to arresting or
ameliorating a disease or at least one of the clinical symptoms of
a disease or disorder, reducing the risk of acquiring a disease or
at least one of the clinical symptoms of a disease, reducing the
development of a disease or at least one of the clinical symptoms
of the disease or reducing the risk of developing a disease or at
least one of the clinical symptoms of a disease. "Treating" or
"treatment" also refers to inhibiting the disease, either
physically, (e.g., stabilization of a discernible symptom),
physiologically, (e.g., stabilization of a physical parameter), or
both, and to inhibiting at least one physical parameter or
manifestation that may or may not be discernible to the patient. In
certain embodiments, "treating" or "treatment" refers to delaying
the onset of the disease or at least one or more symptoms thereof
in a patient who may be exposed to or predisposed to a disease or
disorder even though that patient does not yet experience or
display symptoms of the disease.
"Tregs" or "Treg cells" refer to regulatory T-cells. Regulatory
T-cells are a class of T-cells that suppress the activity of other
immune cells and are defined using flow cytometry by the cell
marker phenotypes CD4+/CD25+/FOXP3+, CD4+CD25+CD127lo, or
CD4+/CD25+/FOXP3+/CD127lo. Because FOXP3 is an intracellular
protein and requires cell fixation and permeabilization for
staining, the cell surface phenotype CD4+CD25+CD127lo- can be used
for defining live Tregs. Tregs also include various Treg
subclasses, such as tTregs (thymus-derived) and pTregs
(peripherally-derived, differentiated from naive T-cells in the
periphery). All Tregs express the IL-2R.alpha..beta..gamma.c
receptor, do not produce IL-2 and are dependent on IL-2 for growth.
Tregs are more potently activated by an
IL-2R.alpha..beta..gamma.c-biased agonist. Treg cells are
characterized by expression of the .alpha.-subunit of the IL-2
receptor (CD25) and the transcription factor forkhead box P3
(FOXP3) and play a critical role in the induction and maintenance
of peripheral self-tolerance to antigens, including those expressed
by tumors. Treg cells require IL-2 for their function and
development and induction of their suppressive characteristics.
"CD4+ T cells" are a type of lymphocyte that functions to
coordinate the immune response by stimulating other immune cells
such as macrophages, B lymphocytes (B cells), CD8 lymphocytes (CD8
cells) to fight infection. CD4+ T cells recognize peptides
presented on MHC Class II molecules, which are found on
antigen-presenting cells.
"CD8+(cytotoxic) T-cells" are generated in the thymus and express
the T-cell receptor. Cytotoxic T-cells express a dimeric
co-receptor, CD8, which typically comprises one CD8.alpha. and one
CD8.beta. chain. CD8+ T-cells recognize peptides presented by MHC
Class 1 molecules found on all nucleated cells. The CD8 heterodimer
binds to a conservative portion of MHC Class 1 during
T-cell/antigen presenting cell interactions. CD8+ T-cells
(cytotoxic T lymphocytes, or CTLs) are important for immune defense
against intracellular pathogens including viruses and bacteria, and
for tumor surveillance.
"Functional activation of Treg cells" is defined as an
IL-2-mediated response in Tregs. Assays for functional activation
of Treg cells include stimulation of pSTAT5, Treg cell
proliferation, and stimulation of the levels of Treg effector
proteins.
"Polypeptide" refers to a molecule composed of monomers (amino
acids) linearly linked by amide bonds (also known as peptide
bonds). The term "polypeptide" refers to any chain of two or more
amino acids and does not refer to a specific length of the product.
Thus, peptides, dipeptides, tripeptides, oligopeptides, "protein,"
"amino acid chain," or any other term used to refer to a chain of
two or more amino acids, are included within the definition of
"polypeptide," and the term "polypeptide" may be used instead of,
or interchangeably with any of these terms. The term "polypeptide"
is also intended to refer to the products of post-expression
modifications of the polypeptide including, for example,
glycosylation, acetylation, phosphorylation, amidation,
derivatization by known protecting/blocking groups, proteolytic
cleavage, and/or modification by non-naturally occurring amino
acids. A polypeptide may be derived from a natural biological
source or produced by recombinant technology but is not necessarily
translated from a designated nucleic acid sequence. A polypeptide
may be generated in any manner, including by recombinant methods or
by chemical synthesis. A polypeptide may have, for example, more
than 100 amino acids, more than 200 amino acids, more than 500
amino acids, more than 1,000 amino acids, or more than 2,000 amino
acids. Polypeptides may have a defined three-dimensional structure,
although they do not necessarily have such structure. Polypeptides
with a defined three-dimensional structure are referred to as
folded, and polypeptides which do not possess a defined
three-dimensional structure, but rather can adopt a large number of
different conformations and are referred to as unfolded.
"Polynucleotide" refers to an isolated nucleic acid molecule or
construct, e.g., messenger RNA (mRNA), virally-derived RNA, or
plasmid DNA (pDNA). A polynucleotide may comprise a conventional
phosphodiester bond or a non-conventional bond, such as an amide
bond, such as found in peptide nucleic acids (PNA).
"Nucleic acid molecule" refers to any one or more nucleic acid
segments, such as DNA or RNA fragments, present in a
polynucleotide.
"Vector" or "expression vector" is synonymous with "expression
construct" and refers to a DNA molecule that is used to introduce
and direct the expression of a specific gene to which it is
operably associated in a target cell. A vector can be a
self-replicating nucleic acid structure as well as a vector
incorporated into the genome of a host cell into which it has been
introduced. An expression vector can comprise an expression
cassette. Expression vectors allow transcription of large amounts
of stable mRNA. Once an expression vector is inside the target
cell, the ribonucleic acid molecule or protein that is encoded by
the gene is produced by the cellular transcription and/or
translation machinery. An expression vector can comprise an
expression cassette that comprises polynucleotide sequences that
encode an IL-2R.beta..gamma.c ligand or IL-2R.beta..gamma.c ligand
construct provided by the present disclosure.
"Host cell," "host cell line," and "host cell culture" refer to
cells into which are exogenous nucleic acid has been introduced,
including the progeny of such cells. Host cells include, for
example, "transformants" and "transformed cells," which include the
primary transformed cell and progeny derived from the primary
transformed cell without regard to the number of passages.
"Antibody" in the broadest sense encompasses various antibody
structures including, for example, monoclonal antibodies,
polyclonal antibodies, multi-specific antibodies such as bispecific
antibodies, and antibody fragments that exhibit a desired antigen
binding activity.
"Full-length antibody," "intact antibody," and "whole antibody"
refer to an antibody having a structure substantially similar to a
native antibody structure or having heavy chains that contain both
Fab and an Fc region.
"Antibody fragment" refers to a molecule other than an intact
antibody that comprises a portion of an intact antibody that binds
the antigen to which the intact antibody binds. Examples of
antibody fragments include Fv, Fab, Fab', Fab'-SH, F(ab')2,
diabodies, linear antibodies, single-chain antibody molecules such
as scFv, and multi-specific antibodies formed from antibody
fragments. Diabodies are antibody fragments with two antigen
binding sites that may be bivalent or bispecific. Antibody
fragments can be made by various techniques, including but not
limited to proteolytic digestion of an intact antibody as well as
production by recombinant host cells such as E. coli or phage.
"Fab" or "Fab region" refers to a polypeptide that comprises the
VH, CHI, VL, and CL immunoglobulin domains, generally on two
different polypeptide chains such as VH--CH on one chain and VL-CL
on the other. Fab may refer to this region in isolation, or this
region in the context of a bispecific antibody. In the context of a
Fab, the Fab comprises an Fv region in addition to the CHI and CL
domains.
"Fv" or "Fv fragment" or "Fv region" refers to a polypeptide that
comprises the VL and VH domains of an antibody (Fab). Fv regions
can be formatted as both Fabs (generally two different polypeptides
that also include the constant regions) and scFvs, where the vi and
vh domains are combined (generally with a linker as discussed) to
form an scFv.
"Single chain Fv" or "scFv" refers to a variable heavy domain
covalently attached to a variable light domain, generally using a
scFv linker as discussed herein, to form a scFv or scFv domain. A
scFv domain can be in either orientation from N- to C-terminus.
"Effector function" refers to a biochemical event that results from
the interaction of an antibody Fc region with an Fc receptor or
ligand. Effector functions include, for example, antibody-dependent
cellular toxicity (ADCC), antibody-dependent cellular phagocytosis
(ADCP), and complement-dependent cytotoxicity (CDC).
"Fc" or "Fc region" or "Fc chain" refers to polypeptide comprising
the constant region of an antibody, in some instances, excluding
all or a portion of the first constant region immunoglobulin domain
(e.g., CHI) or a portion thereof, and in some cases, further
excluding all or a portion of the hinge. Thus, an Fc can refer to
the last two constant region immunoglobulin domains (e.g., CH2 and
CH3) of IgA, IgD, and IgG, the last three constant region
immunoglobulin domains of IgE and IgM, and optionally, all or a
portion of the flexible hinge N-terminal to these domains. For IgA
and IgM, Fc may include the J chain. For IgG, the Fc chain
comprises immunoglobulin domains CH2 and CH3 (Cy2 and Cy3), and
optionally all or a portion of the hinge region between CHI (Cy1)
and CH2 (Cy2). Although the boundaries of the Fc region may vary,
the human IgG heavy chain Fc region is usually defined to include
residues E216, C226, or A231 to its carboxyl-terminus, wherein the
numbering is according to the EU index as in Kabat. An amino acid
modification can be made to the Fc region, for example to alter
binding to one or more FcyR or to the FcRn. In EU numbering for
human IgG1, the CH2-CH3 domain comprises amino acids 231 to 447,
and the hinge is 216 to 230. Thus, the definition of Fc chain
includes both amino acids 231-447 (CH2-CH3) or 216-447
(hinge-CH2-CH3), or fragments thereof. An Fc fragment can contain
fewer amino acids from either or both of the N- and C-termini that
retains the ability to form a dimer with another Fc chain or Fc
fragment as can be detected using standard methods, generally based
on size (e.g., non-denaturing chromatography, size exclusion
chromatography, etc.). Human IgG Fc chains are of particular use,
and can be the Fc chain from human IgG1, IgG2 or IgG4.
"Heavy constant region" refers to the CH1-hinge-CH2-CH3 portion of
an antibody or fragments thereof, excluding the variable heavy
domain; in EU numbering of human IgG1, such as amino acids 118-447.
"Heavy chain constant region fragment" refers to a heavy chain
constant region that contains fewer amino acids from either or both
of the N- and C-termini that retains the ability to form a dimer
with another heavy chain constant region.
"Immunoglobulin molecule" refers to a protein having the structure
of a naturally occurring antibody. For example, immunoglobulins of
the IgG class are heterotetrameric glycoproteins of about 150,000
Da, composed of two light chains and two heavy chains that are
bonded together through disulfide bonds. From N- to C-terminus,
each heavy chain has a variable region (VH), also called a variable
heavy domain or a heavy chain variable domain, followed by three
constant domains (CHI, CH2, and CH3), also called a heavy chain
constant region. Similarly, from N- to C-terminus, each light chain
has a variable region (VL), also called a variable light domain or
a light chain variable domain, followed by a constant light (CL)
domain, also called a light chain constant region. The heavy chain
of an immunoglobulin may be assigned to one of five classes, called
a (IgA), Ii (IgD), E (IgE), y (IgG), or .mu. (IgM), some of which
may be further divided into subclasses, e.g., .gamma.1 (IgG1),
.gamma.2 (IgG2), .gamma.3 (IgG3), .gamma.4 (gG4), .alpha.1 (IgA1)
and .alpha.2 (IgA2). The light chain of an immunoglobulin may be
assigned to one of two types, kappa (.kappa.) or lambda (L), based
on the amino acid sequence of its constant domain. An
immunoglobulin essentially consists of two Fab molecules and an Fc
chain, linked via the immunoglobulin hinge region.
"Immunoconjugate" refers to a polypeptide molecule that includes at
least one IL-2R.beta..gamma.c ligand and at least one antigen
binding moiety. An immunoconjugate can comprise at least one
IL-2R.beta..gamma.c ligand, and at least two antigen binding
moieties. An immunoconjugate can comprise at least one
IL-2R.beta..gamma.c ligand and two antigen binding moieties joined
by one or more linker sequences. An antigen binding moiety can be
joined to the IL-2R.beta..gamma.c ligand by a variety of
interactions and in a variety of configurations.
"Amino acid sequence similarity" refers to an amino acid sequence
in which one or more amino acids of the amino has been replaced
with a chemically similar amino acid. Examples of chemically
similar amino acids include (a) amino acids having a small
hydrophobic side chain such as alanine (A), glycine (G), proline
(P), serine (S), or threonine (T); (b) amino acids having a
hydroxyl-containing side chain such as serine (S), threonine (T),
or tyrosine (Y); (c) amino acids having an acidic side chain such
as aspartate (D) or glutamate (E); (d) amino acids having a
polar-neutral side chain such as histidine (H), asparagine (N),
glutamine (Q), serine (S), threonine (T), or tyrosine (Y); (e)
amino acids having a basic side chain such as arginine (R), lysine
(K), or histidine (H); (f) amino acids having a large hydrophobic
side chain such as isoleucine (I), leucine (L), methionine (M),
valine (V), phenylalanine (F), tyrosine (Y), or tryptophan (W); and
(g) amino acids having an aromatic side chain comprising
phenylalanine (F), histidine (H), tryptophan (W), or tyrosine (Y).
A chemically similar amino acid can comprise a naturally occurring
amino acid or a non-natural amino acid.
"Percent (%) sequence similarity" refers to amino acid sequences in
which one or more amino acids of a reference amino acid sequence is
replaced with an amino acid such as a chemically similar amino
acid. For example, given a reference amino acid sequence
-RDQYYPCWMAQLGELCDLDEVF-(SEQ ID NO: 1037), the amino acid sequence
-RDQYYPCYMAQLGELCDLEEVF-(SEQ ID NO: 1038) represents a similar
amino acid sequence, in which an amino acid W having aromatic side
chain is replaced with chemically similar amino acid Y having an
aromatic side chain; and an amino acid D having an acidic side
chain is replaced with chemically similar amino acid E having an
acidic side chain. Referring to this example, the similar amino
acid sequence, which consists of 22 amino acids, has a 90.9% (2/22)
sequence similarity to the reference amino acid sequence.
"Percent (%) sequence similarity" is determined by comparing the
number of amino acids that are the same in a subject peptide ligand
and a reference peptide ligand. A peptide ligand provided by the
present disclosure can comprise, for example, greater than 70%,
greater than 80%, or greater than 90% sequence similarity to a
reference peptide ligand. For example, based on a reference peptide
ligand having SEQ ID NO: 1030, peptide ligands having SEQ-ID NOS:
1031-1036, have either 1, 2, 3, 4, or 5 amino acid in which an
amino acid of the reference peptide has been substituted or
replaced with the amino acid, alanine. Peptide ligands having SEQ
ID NOS: 1031-1036 are characterized by a 95%, 90%, 85%, 80%, 75%,
or 70% sequence similarity, respectively, to the amino acid
sequence of the reference peptide.
TABLE-US-00001 SEQ ID NO: 1030 Y P C W L A R V G E L C D L D S G D
V H SEQ ID NO: 1031 A P C W L A R V G E L C D L D S G D V H SEQ ID
NO: 1032 A P C A L A R V G E L C D L D S G D V H SEQ ID NO: 1033 A
P C A L A A V G E L C D L D S G D V H SEQ ID NO: 1034 A P C A L A A
V G A L C D L D S G D V H SEQ ID NO: 1035 A P C A L A A V G A L C D
L A S G D V H SEQ ID NO: 1036 A P C A L A A V G A L C D L A A G D V
H
A peptide ligand provided by the present disclosure can have an
amino acid sequence in which from 1 to 5 amino acids of a reference
amino acid sequence is substituted with another amino acid.
For example, a peptide ligand derived from a reference peptide
ligand can have from 1 to 5 amino acid substitutions, from 1 to 4,
from 1 to 3, or from 1 to 2 amino acid substitutions. For example,
a peptide ligand derived from a reference peptide ligand can have 1
amino acid substitution, 2 amino acid substitutions, 3 amino acid
substitutions, 4 amino acid substitutions, or 5 amino acid
substitutions.
An amino acid substitution can be independent of the other amino
acid substitutions.
Each amino acid substitution can independently be a conservative
amino acid substitution or a non-conservative amino acid
substitution.
A conservative amino acid substitution refers to one of the
following amino acid substitutions: amino acids having a small
hydrophobic side chain comprising alanine (A), glycine (G), proline
(P), serine (S), or threonine (T); amino acids having a
hydroxyl-containing side chain comprising serine (S), threonine
(T), or tyrosine (Y); amino acids having an acidic side chain
comprising aspartate (D) or glutamate (E); amino acids having a
polar-neutral side chain comprising histidine (H), asparagine (N),
glutamine (Q), serine (S), threonine (T), or tyrosine (Y); amino
acids having a basic side chain comprising arginine (R), lysine
(K), or histidine (H); amino acids having a large hydrophobic side
chain comprising isoleucine (I), leucine (L), methionine (M),
valine (V), phenylalanine (F), tyrosine (Y), or tryptophan (W); and
amino acids having an aromatic side chain comprising phenylalanine
(F), histidine (H), tryptophan (W), or tyrosine (Y).
For example, a reference peptide ligand can have the amino acid
sequence of SEQ ID NO: 1020.
TABLE-US-00002 SEQ ID NO: 1020 Y W C W M A Q V G E L C D L SEQ ID
NO: 1021 Y H C W M A Q V G E L C D L SEQ ID NO: 1022 Y H C W M G Q
V G E L C D L SEQ ID NO: 1023 Y H C W M G Q M G E L C D L SEQ ID
NO: 1024 Y H C W M G Q M G E L C E L SEQ ID NO: 1025 Y H C W M G Q
M G E L C E M
Peptide ligands having SEQ ID NOS: 1021-1025 represent peptide
ligands in which the reference peptide ligand having SEQ ID NO:
1020 has been substituted with from 1 to 5 conservative amino acid
substitutions, respectively.
A peptide ligand provided by the present disclosure can comprise a
truncated peptide ligand. A truncated peptide ligand refers to a
peptide ligand in which from 1 to 5 amino acids have independently
been removed from the N-terminus, the C-terminus, or from both the
N-terminus and the C-terminus of the corresponding reference
peptide ligand. A truncated peptide ligand derived from the
corresponding reference peptide ligand can independently have from
1 to 5 amino acids, such as from 1 to 4 amino acids, from 1 to 3
amino acids, or from 1 to 2 amino acids independently removed from
the N-terminus, the C-terminus, or from both the N-terminus and the
C-terminus of the reference peptide ligand. A truncated peptide
ligand derived from the corresponding reference peptide ligand can
independently have 1 amino acid, 2 amino acids, 3 amino acids, 4
amino acids, or 5 amino acids removed from the N-terminus, the
C-terminus, or from both the N-terminus and the C-terminus of the
reference peptide ligand.
For example, a reference peptide ligand can have the amino acid
sequence of SEQ ID. NO: 1000. Examples of truncated peptide ligands
derived from the reference peptide ligand of SEQ ID. NO: 1000
include truncated peptide ligands of amino acid sequence of SEQ ID
NOS: 1001-1008.
TABLE-US-00003 SEQ ID NO: 1000 M G F Y P C W T A Q L G E L C D L S
V D SEQ ID NO: 1001 G F Y P C W T A Q L G E L C D L S V D SEQ ID
NO: 1002 F Y P C W T A Q L G E L C D L S V D SEQ ID NO: 1003 Y P C
W T A Q L G E L C D L S V D SEQ ID NO: 1004 M G F Y P C W T A Q L G
E L C D L S V SEQ ID NO: 1005 M G F Y P C W T A Q L G E L C D L S
SEQ ID NO: 1006 M G F Y P C W T A Q L G E L C D L SEQ ID NO: 1007 G
F Y P C W T A Q L G E L C D L S V SEQ ID NO: 1008 F Y P C W T A Q L
G E L C D L
The truncated peptide ligands of SEQ ID NOS: 1001-1003 have amino
acids removed from the N-terminus of the reference peptide ligand;
truncated peptide ligands of SEQ ID NOS: 1004-1006 have amino acids
removed from the C-terminus of the reference peptide ligand; and
truncated peptide ligands of SEQ ID NOS: 1007-1008 have amino acids
removed from both the N-terminus and from the C-terminus of the
reference peptide ligand.
As another example, a reference peptide ligand can comprise an
amino acid sequence of Formula (A):
--X.sup.500--X.sup.501--C--X.sup.502--X.sup.503--X.sup.504--X.sup.505--X.-
sup.506--X.sup.507--X.sup.508--X.sup.509--C--X.sup.510--X.sup.511
(A) where each --X-- independently represents an amino acid. Amino
acid sequences of Formula (A1)-(A2) represent truncated peptide
ligands derived from the reference peptide ligand comprising the
amino acid sequence of Formula (A):
--X.sup.501--C--X.sup.502--X.sup.503--X.sup.504--X.sup.505--X.sup.506--X.-
sup.507--X.sup.508--X.sup.509--C--X.sup.510--X.sup.511-- A1)
--C--X.sup.502--X.sup.503--X.sup.504--X.sup.505--X.sup.506--X.sup.507--X.-
sup.508--X.sup.509--C--X.sup.510--X.sup.511 (A2)
--C--X.sup.502--X.sup.503--X.sup.504--X.sup.505--X.sup.506--X.sup.507--X.-
sup.508--X.sup.509--C-- (A3)
--X.sup.502--X.sup.503--X.sup.504--X.sup.505--X.sup.506--X.sup.507--X.sup-
.508--X.sup.509--C--X.sup.510-- (A4)
--X.sup.502--X.sup.503--X.sup.504--X.sup.505--X.sup.506--X.sup.507--X.sup-
.508--X.sup.509-- (A5)
A peptide ligand provided by the present disclosure can comprise an
amino acid sequence in which from 1 to 3 glycines are independently
bonded to the N-terminus, to the C-terminus, or to both the
N-terminus and to the C-terminus of a reference peptide ligand.
TABLE-US-00004 SEQ ID NO: 1010 K Y C G F A Q L G E L C V L SEQ ID
NO: 1011 G K Y C G F A Q L G E L C V L SEQ ID NO: 1012 G G K Y C G
F A Q L G E L C V L SEQ ID NO: 1013 G G G K Y C G F A Q L G E L C V
L SEQ ID NO: 1014 K Y C G F A Q L G E L C V L G SEQ ID NO: 1015 K Y
C G F A Q L G E L C V L G G SEQ ID NO: 1016 K Y C G F A Q L G E L C
V L G G G SEQ ID NO: 1017 G K Y C G F A Q L G E L C V L G SEQ ID
NO: 1018 G G K Y C G F A Q L G E L C V L G
For example, reference peptide ligand can have SEQ ID NO: 1010.
Peptide ligands having SEQ ID NOS: 1011-1013 have from 1 to 3
glycines bonded to the N-terminus of the reference peptide ligand,
respectively; peptide ligands having SEQ ID NOS: 1014-1016 have
from 1 to 3 glycines bonded to the C-terminus of the reference
peptide ligand, respectively; and peptide ligands having SEQ ID
NOS: 1017-1018 independently have 1 or 2 glycines bonded to both
the N-terminus and to the C-terminus of the reference peptide
ligand.
A peptide ligand can comprise a truncated peptide ligand in which
from 1 to 3 glycines are independently bonded to the N-terminus, to
the C-terminus, or to both the N-terminus and to the C-terminus of
a reference truncated peptide ligand.
"IL-2R.alpha. binding compound" refers to an IL-2R.alpha. ligand
provided by the present disclosure, a tandem IL-2R.alpha. ligand
provided by the present disclosure, an IL-2R.alpha. ligand
construct provided by the present disclosure, and a construct
comprising at least one IL-2R.alpha. ligand and at least one
IL-2R.beta. ligand and/or at least one IL-2R.gamma.c ligand.
The expression "at least one" refers to "one or more." For example,
the expression at least can refer to from 1 to 10, from 1 to 8,
from 1 to 6, from 1 to 5, from 1 to 4, from 1 to 3, or from 1 to 2.
For example, the expression at least one can refer to 1, 2, 3, 4,
5, 6, 7, 8, 9, or 10.
Reference is now made in detail to certain embodiments of
compounds, compositions, and methods. The disclosed embodiments are
not intended to be limiting of the claims. To the contrary, the
claims are intended to cover all alternatives, modifications, and
equivalents.
IL-2R.alpha. ligands provided by the present disclosure comprise
peptide domains amenable to strategies to simultaneously mask
peripheral bioactivity, target delivery to a tumor, selectively
activate cytotoxic anti-tumor cells, and direct IL-2 receptor
activation at tumor sites. IL-2R agonists provided by the present
disclosure can also be used to treat autoimmune diseases.
IL-2R agonists can be designed to selectively activate a specific
form of the IL-2 receptor. The small peptide IL-2R ligands, having
an amino acid sequence that is unrelated to that of the natural
cytokine, can selectively bind to and activate the IL-2R.alpha.
subunit to produce therapeutic IL-2 activity. Because the IL-2R
peptidyl ligands are small, i.e. from 5 to 20 amino acids, with
very low immunogenic potential, the small peptidyl IL-2R ligands
can be incorporated into compounds to enhance therapeutic efficacy.
For example, this allows the affinity of the IL-2R peptidyl ligands
for each of the three IL-2R subunits to be tuned to direct the
responsiveness of a particular immune cell population and affords
flexibility to chemically target to tumor sites and mediate the
immune response.
IL-2R.beta. and IL-2R.gamma.c ligands and compounds comprising
IL-2R.beta. and IL-2R.gamma.c ligands are disclosed in U.S.
Provisional Application No. 62/715,097 filed on Aug. 6, 2018, which
is incorporated by reference in its entirety.
The present disclosure is directed to IL-2R.alpha. ligands and
compounds comprising IL-2R.alpha. ligands. The compounds comprising
IL-2R.alpha. ligands can comprise an IL-2R.beta. ligand and/or an
IL-2R.gamma.c ligand.
Peptides having a binding affinity to IL-2R.alpha. can be
identified by random peptide diversity generating systems in
conjunction with an affinity enrichment process, for example, using
peptides on plasmids or peptides on phage systems.
Peptidyl ligands for the IL-2R.alpha. subunit can be identified
from highly complex peptide diversity libraries such as phage
display libraries, optimized by peptide synthesis, and can be
assembled into monomers, homo-oligomers, heteromers or incorporated
into other compounds.
Random peptides can be presented either on the surface of a phage
particle, as part of a fusion protein comprising either the pIII or
the pVIII coat protein of a phage fd derivative (peptides on phage)
or as a fusion protein with the LacI peptide fusion protein bound
to a plasmid (peptides on plasmids). The phage or plasmids,
including the DNA encoding the peptides, can be identified and
isolated by an affinity enrichment process using an immobilized
IL-2R.alpha. subunit. The affinity enrichment process, sometimes
referred to as "panning," involves multiple rounds of incubating
the phage or plasmids with the immobilized receptor, collecting the
phage or plasmids that bind to the receptor (along with the
accompanying DNA), and producing more of the phage or plasmids
(along with the accompanying LacI-peptide fusion protein)
collected. The extracellular domain (ECD) of the IL-2R.alpha.
subunit can be used during panning.
After several rounds of affinity enrichment, the phage or plasmids
and accompanying peptides were examined by ELISA to determine if
the peptides bind specifically to the IL-2R.alpha. subunit. The
assay can be performed using methods similar to those described for
the affinity enrichment process, except that after removing unbound
phage, the wells can be treated with an antibody such as a rabbit
anti-phage antibody and then with alkaline phosphatase
(AP)-conjugated goat anti-rabbit antibody. The amount of alkaline
phosphatase in each well can be determined by standard methods.
By comparing test wells with control wells without the IL-2
receptor, one can determine whether the fusion proteins bind to the
receptor specifically. The phage pools found to bind to the
IL-2R.alpha. subunit can be screened in a colony lift probing
format using monovalent or divalent receptor.
IL-2R.alpha. ligands can also be identified by panning subunits
fused to Fc.
Peptides found to bind specifically to the IL-2R.alpha. subunit can
then be synthesized as the free peptide (e.g., no phage) and tested
in a blocking assay. The blocking assay can be carried out in a
similar manner to the ELISA, except that IL-2R.alpha. binding
peptides or a reference peptide at different concentrations can be
added to the wells before the tracer peptide or fusion protein (the
control wells can be of two types: (1) no receptor; and (2)
IL-2R.alpha. subunit binding peptide or reference peptide). Tracer
peptides or fusion protein in the instance comprise IL-2R.alpha.
ligands wherein binding to immobilized IL-2R.alpha. can be detected
by a variety of means.
The IL-2 receptor, as well as its extracellular domain, can be
produced in recombinant host cells.
Screening methods used to identify peptides that bind to
IL-2R.alpha. can involve first identifying lead peptides which bind
to the extracellular domain of the receptor and then synthesizing
other peptides which resemble the lead peptides. Specifically,
using a pIII or pVIII-based peptides on a phage system, a random
library can be screened to discover a phage that presents a peptide
that binds to the IL-2R.alpha. subunit. The phage DNAs are
sequenced to determine the sequences of the peptides displayed on
the surface of the phages.
For example, clones capable of specific binding to IL-2R.alpha. can
be identified from a random linear or disulfide-bridged cyclic
10-mer pVIII library and a random linear or disulfide-bridged
cyclic 12-mer pVIII library. The sequences of these peptides can
serve as the basis for the construction of other peptide libraries
designed to contain a high frequency of derivatives of the
initially identified peptides. These libraries can be synthesized
so as to favor the production of peptides that differ from the
binding peptide in only a few residues. This approach involves the
synthesis of an oligonucleotide with the binding peptide coding
sequence, except that rather than using pure preparations of each
of the four nucleoside triphosphates in the synthesis, mixtures of
the four nucleoside triphosphates (i.e., 55% of the "correct"
nucleotide, and 15% each of the other three nucleotides is one
preferred mixture for this purpose and 70% of the "correct"
nucleotide and 10% of each of the other three nucleotides is
another preferred mixture for this purpose) can be used so as to
generate derivatives of the binding peptide coding sequence.
A variety of strategies can be used to derivatize the lead peptides
by making "mutagenesis on a theme" libraries, including a pVIII
phagemid mutagenesis library based on the consensus sequence and
mutagenized at 70:10:10:10 frequency with 5 NNK codons on each
terminus (probing with radiolabeled monovalent receptor and with or
without peptide elution).
The "peptides on plasmids" method can also be used for peptide
screening and mutagenesis studies. According to this approach,
random peptides can be fused at the C-terminus of LacI through
expression from a plasmid vector carrying the fusion gene. Linkage
of the LacI-peptide fusion to its encoding DNA occurs via the lacO
sequences on the plasmid, forming a stable peptide-LacI-plasmid
complex that can be screened by affinity purification (panning) on
an immobilized receptor. The plasmids thus isolated can then be
reintroduced into E. coli by electroporation to amplify the
selected population for additional rounds of screening, or for the
examination of individual clones.
In addition, random peptide screening and mutagenesis studies can
be performed using a modified C-terminal Lac-I display system in
which display valency was reduced ("headpiece dimer" display
system). The libraries can be screened, and the resulting DNA
inserts were cloned as a pool into a maltose binding protein (MBP)
vector allowing their expression as a C-terminal fusion protein.
Crude cell lysates from randomly picked individual MBP fusion
clones were then assayed for IL-2R.alpha. binding in an ELISA
format, as discussed above.
A variety of methods can be used to evaluate IC.sub.50 values. For
example, an equilibrium binding ELISA assay, an IL-2 or
IL-2R.alpha. peptide tracer, was used to determine whether the
peptides inhibit the binding of the tracer to the extracellular
domain of IL-2.alpha.. The IC.sub.50 value can be determined using
the free peptide, which optionally can be C-terminally amidated, or
can be prepared as an ester or other carboxy amide. To recreate the
exact sequence displayed by the phage, the N-terminal and
C-terminal amino acids of the synthetic peptides are often preceded
by one or two glycine residues. These glycines are not believed to
be necessary for binding or activity.
Synthetic peptide library technologies such as DNA-encoded peptide
libraries can also be used.
In general, peptides and peptidomimetics having an IC.sub.50 of
greater than 100 .mu.M lack sufficient binding affinity to be
useful in imaging, targeting, diagnostic, and therapeutic
applications. For imaging, targeting or diagnostic purposes,
peptides and peptidomimetics can have an IC.sub.50, for example, of
1 .mu.M or less and, for pharmaceutical purposes, peptides and
peptidomimetics can have an IC.sub.50, for example, less than 100
.mu.m, or less than 100 nm.
An IL-2R.alpha. ligand provided by the present disclosure can bind
to the human IL-2R.alpha. subunit with an IC.sub.50, for example,
of less than 100 .mu.M, less than 10 .mu.M, less than 1 .mu.M, less
than 0.1 .mu.M, or less than 0.01 .mu.M.
An IL-2R.alpha. ligand provided by the present disclosure can bind
to the human IL-2R.alpha. subunit with an IC.sub.50, for example,
from 1 .mu.M to 100 .mu.M, from 10 .mu.M to 10 .mu.M, from 100
.mu.M to 1 .mu.M, from, 0.001 .mu.M to 1 .mu.M, or from 0.01 .mu.M
to 1 .mu.M.
An IL-2R.alpha. ligand provided by the present disclosure can bind
to a mammalian IL-2R.alpha. subunit with an IC.sub.50, for example,
of less than 100 .mu.M, less than 10 .mu.M, less than 1 .mu.M, less
than 0.1 .mu.M, or less than 0.01 .mu.M.
An IL-2R.alpha. ligand provided by the present disclosure can bind
to a mammalian IL-2R.alpha. subunit with an IC.sub.50, for example,
from 1 .mu.M to 100 .mu.M, from 10 .mu.M to 10 .mu.M, from 100
.mu.M to 1 .mu.M, from, 0.001 .mu.M to 1 .mu.M, or from 0.01 .mu.M
to 1 .mu.M.
An IL-2R.alpha. ligand provided by the present disclosure can have
an amino acid sequence of any one of SEQ ID NOS: 1-307 and
400-423.
An IL-2R.alpha. ligand provided by the present disclosure can have
greater than 70% sequence similarity, greater than 75% sequence
similarity, greater than 80%, greater than 85% sequence similarity,
greater than 90% sequence similarity, or greater than 95% sequence
similarity to any one of SEQ ID NOS: 1-307 and 400-423.
IL-2R.alpha. ligands provided by the present disclosure can
comprise the amino acid sequence of Formula (1) (SEQ ID NO: 1):
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12-- (1)
wherein, X.sup.1 can be selected from an amino acid comprising a
large hydrophobic side chain or an aromatic side chain; X.sup.2 can
be selected from an amino acid comprising a large hydrophobic side
chain; X.sup.3 can be selected from an amino acid; X.sup.4 can be
selected from an amino acid comprising a large hydrophobic side
chain; X.sup.5 can be selected from an amino acid comprising a
small hydrophobic side chain or a polar/neutral side chain; X.sup.6
can be selected from an amino acid comprising a large hydrophobic
side chain; X.sup.7 can be selected from an amino acid comprising a
large hydrophobic side chain; X.sup.8 can be selected from an amino
acid comprising a large hydrophobic side chain; X.sup.9 can be
selected from an amino acid comprising a small hydrophobic side
chain; X.sup.10 can be selected from an amino acid comprising a
polar/neutral side chain; X.sup.11 can be selected from an amino
acid comprising a large hydrophobic side chain; and X.sup.12 can be
selected from an amino acid comprising a large hydrophobic side
chain.
In IL-2R.alpha. ligands of Formula (1), X.sup.1 can be selected
from F, H, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (1), X.sup.2 can be selected
from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (1), X.sup.3 can be selected
from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and
Y.
In IL-2R.alpha. ligands of Formula (1), X.sup.4 can be selected
from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (1), X.sup.5 can be selected
from H, N, Q, Y, A, G, P, S, and T.
In IL-2R.alpha. ligands of Formula (1), X.sup.6 can be selected
from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (1), X.sup.7 can be selected
from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (1), X.sup.9 can be selected
from A, G, P, S, and T.
In IL-2R.alpha. ligands of Formula (1), X.sup.10 can be selected
from H, N, Q, S, T, and Y.
In IL-2R.alpha. ligands of Formula (1), X.sup.11 can be selected
from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (1), X.sup.12 can be selected
from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (1), X.sup.1 can be selected
from L, W, and F.
In IL-2R.alpha. ligands of Formula (1), X.sup.2 can be selected
from D, A, L, and V.
In IL-2R.alpha. ligands of Formula (1), X.sup.3 can be selected
from L, V, H, P, and E.
In IL-2R.alpha. ligands of Formula (1), X.sup.4 can be selected
from T, D, and W.
In IL-2R.alpha. ligands of Formula (1), X.sup.5 can be selected
from Y, W, P, and Q.
In IL-2R.alpha. ligands of Formula (1), X.sup.6 can be selected
from D, S, V, and A.
In IL-2R.alpha. ligands of Formula (1), X.sup.7 can be selected
from E and Y.
In IL-2R.alpha. ligands of Formula (1), X.sup.8 can be selected
from L and F.
In IL-2R.alpha. ligands of Formula (1), X.sup.9 can be selected
from L, R, and S.
In IL-2R.alpha. ligands of Formula (1), X.sup.10 can be selected
from A, R, and Q.
In IL-2R.alpha. ligands of Formula (1), X.sup.11 can be selected
from C, R, V, and M.
In IL-2R.alpha. ligands of Formula (1), X.sup.12 can be selected
from T, L, and M.
In IL-2R.alpha. ligands of Formula (1), X.sup.1 can be F.
In IL-2R.alpha. ligands of Formula (1), X.sup.2 can be selected
from L and V.
In IL-2R.alpha. ligands of Formula (1), X.sup.3 can be selected
from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and
Y.
In IL-2R.alpha. ligands of Formula (1), X.sup.4 can be W.
In IL-2R.alpha. ligands of Formula (1), X.sup.5 can be P.
In IL-2R.alpha. ligands of Formula (1), X.sup.6 can be V.
In IL-2R.alpha. ligands of Formula (1), X.sup.7 can be Y.
In IL-2R.alpha. ligands of Formula (1), X.sup.8 can be F.
In IL-2R.alpha. ligands of Formula (1), X.sup.9 can be S.
In IL-2R.alpha. ligands of Formula (1), X.sup.10 can be Q.
In IL-2R.alpha. ligands of Formula (1), X.sup.11 can be selected
from N and V.
In IL-2R.alpha. ligands of Formula (1), X.sup.12 can be selected
from L and M.
In IL-2R.alpha. ligands of Formula (1), X.sup.1 can be F, X.sup.4
can be W, X.sup.5 can be P, X.sup.6, can be V, X.sup.7 can be Y,
X.sup.8 can be F, X.sup.9 can be S, and X.sup.10 can be Q.
In IL-2R.alpha. ligands of Formula (1),
X.sup.1 can be F;
X.sup.2 can be selected from F, H, I, L, M, V, W, and Y;
X.sup.3 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.4 can be W;
X.sup.5 can be selected from H, N, Q, Y, A, G, P, S, and T;
X.sup.6 can be V;
X.sup.7 can be Y;
X.sup.8 can be F;
X.sup.9 can be S;
X.sup.10 can be Q;
X.sup.11 can be selected from F, I, L, M, V, W, and Y; and
X.sup.12 can be selected from F, I, L, M, V, W, and Y.
IL-2R.alpha. ligands provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
2 to SEQ ID NO: 6:
TABLE-US-00005 SEQ ID NO: 2 L D L T Y D E L L A C T SEQ ID NO: 3 W
A Y D W S C F R R R L SEQ ID NO: 4 F L H W P V Y F C Q V M SEQ ID
NO: 5 F L P W P V Y F S Q V L SEQ ID NO: 6 F V E W Q A Y F S Q M
M
An IL-2R.alpha. ligand provided by the present disclosure can
comprise a truncated amino acid sequence of any one of SEQ ID NO: 1
to SEQ ID NO: 6.
An IL-2R.alpha. ligands provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
1 to SEQ ID NO: 6, or a truncated amino acid sequence of any one of
SEQ ID NO: 1 to SEQ ID NO: 6, wherein the amino acid sequence can
independently comprise from 1 to 4 glycines (G) (SEQ ID NO: 1041)
on the N-terminus, on the C-terminus, or on both the N- and
C-termini.
An IL-2R.alpha. ligands provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
1 to SEQ ID NO: 6, or a truncated amino acid sequence of any one of
SEQ ID NO: 1 to SEQ ID NO: 6, wherein the amino acid sequence
comprises one or more amino acid substitutions such as from 1 to 5
amino acid substitutions.
IL-2R.alpha. ligands provided by the present disclosure can
comprise the amino acid sequence of Formula (2) (SEQ ID NO: 7):
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12-- (2)
wherein, X.sup.1 can be selected from an amino acid comprising a
large hydrophobic side chain; X.sup.2 can be selected from an amino
acid comprising a large hydrophobic side chain; X.sup.3 can be
selected from an amino acid comprising a small hydrophobic side
chain; X.sup.4 can be selected from an amino acid comprising a
large hydrophobic side chain; X.sup.5 can be selected from an amino
acid comprising an acidic side chain; X.sup.6 can be selected from
an amino acid comprising an acidic side chain; X.sup.7 can be
selected from an amino acid comprising a large hydrophobic side
chain; X.sup.8 can be selected from an amino acid comprising a
large hydrophobic side chain; X.sup.9 can be selected from an amino
acid; X.sup.10 can be selected from an amino acid comprising a
polar/neutral side chain; X.sup.11 can be selected from an amino
acid comprising a large hydrophobic side chain; and X.sup.12 can be
selected from an amino acid comprising a large hydrophobic side
chain.
In IL-2R.alpha. ligands of Formula (2), X.sup.1 can be selected
from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (2), X.sup.2 can be selected
from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (2), X.sup.3 can be selected
from A, G, P, S, and T.
In IL-2R.alpha. ligands of Formula (2), X.sup.4 can be selected
from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (2), X.sup.6 can be selected
from D and E.
In IL-2R.alpha. ligands of Formula (2), X.sup.7 can be selected
from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (2), X.sup.8 can be selected
from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (2), X.sup.9 can be selected
from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and
Y.
In IL-2R.alpha. ligands of Formula (2), X.sup.10 can be selected
from H, N, Q, S, T, and Y.
In IL-2R.alpha. ligands of Formula (2), X.sup.11 can be selected
from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (2), X.sup.12 can be selected
from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (2), X.sup.1 can be F.
In IL-2R.alpha. ligands of Formula (2), X.sup.2 can be selected
from I, L, and V.
In IL-2R.alpha. ligands of Formula (2), X.sup.3 can be P.
In IL-2R.alpha. ligands of Formula (2), X.sup.4 can be W.
In IL-2R.alpha. ligands of Formula (2), X.sup.5 can be selected
from P, D, and E.
In IL-2R.alpha. ligands of Formula (2), X.sup.6 can be selected
from V and E.
In IL-2R.alpha. ligands of Formula (2), X.sup.7 can be Y.
In IL-2R.alpha. ligands of Formula (2), X.sup.8 can be F.
In IL-2R.alpha. ligands of Formula (2), X.sup.9 can be S, A, K, and
L.
In IL-2R.alpha. ligands of Formula (2), X.sup.10 can be Q.
In IL-2R.alpha. ligands of Formula (2), X.sup.11 can be selected
from V, I, and L.
In IL-2R.alpha. ligands of Formula (2), X.sup.12 can be selected
from L and M.
In IL-2R.alpha. ligands of Formula (2), X.sup.1 can be F.
In IL-2R.alpha. ligands of Formula (2), X.sup.2 can be selected
from L and V.
In IL-2R.alpha. ligands of Formula (2), X.sup.3 can be P.
In IL-2R.alpha. ligands of Formula (2), X.sup.4 can be W.
In IL-2R.alpha. ligands of Formula (2), X.sup.5 can be D.
In IL-2R.alpha. ligands of Formula (2), X.sup.6 can be E.
In IL-2R.alpha. ligands of Formula (2), X.sup.7 can be Y.
In IL-2R.alpha. ligands of Formula (2), X.sup.8 can be F.
In IL-2R.alpha. ligands of Formula (2), X.sup.9 can be selected
from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and
Y.
In IL-2R.alpha. ligands of Formula (2), X.sup.9 can be S.
In IL-2R.alpha. ligands of Formula (2), X.sup.10 can be Q.
In IL-2R.alpha. ligands of Formula (2), X.sup.11 can be selected
from I, L, and V.
In IL-2R.alpha. ligands of Formula (2), X.sup.12 can be L.
In IL-2R.alpha. ligands of Formula (2), X.sup.1 can be F, X.sup.3
can be P, X.sup.4 can be W, X.sup.5 can be D, X.sup.6, can be E,
X.sup.7 can be Y, X.sup.8 can be F, X.sup.10 can be Q, and X.sup.12
can be L.
In IL-2R.alpha. ligands of Formula (2),
X.sup.1 can be F;
X.sup.2 can be selected from F, I, L, M, V, W, and Y;
X.sup.3 can be P;
X.sup.4 can be W;
X.sup.5 can be selected from D and P;
X.sup.6 can be E;
X.sup.7 can be Y;
X.sup.8 can be F;
X.sup.9 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.10 can be Q;
X.sup.11 can be selected from F, I, L, M, V, W, and Y; and
X.sup.12 can be L.
IL-2R.alpha. ligands provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
8 to SEQ ID NO: 15:
TABLE-US-00006 SEQ ID NO: 8 F I F A Q A Q L L SEQ ID NO: 9 F I P W
D E Y F K Q V L SEQ ID NO: 10 F V P W D V Y F S Q I L SEQ ID NO: 11
F I P W D E Y F K Q V L SEQ ID NO: 12 F V P W P E Y F L Q I M SEQ
ID NO: 13 F I P W E E Y F S Q L L SEQ ID NO: 14 F I P W P E Y F S Q
L L SEQ ID NO: 15 F V P W D E Y F L Q I L
An IL-2R.alpha. ligand provided by the present disclosure can
comprise a truncated amino acid sequence of any one of SEQ ID NO: 7
to SEQ ID NO: 15.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
7 to SEQ ID NO: 15, or a truncated amino acid sequence of any one
of SEQ ID NO: 7 to SEQ ID NO: 15, wherein the amino acid sequence
can independently comprise from 1 to 4 glycines (G) (SEQ ID NO:
1041) on the N-terminus, on the C-terminus, or on both the N- and
C-termini.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
7 to SEQ ID NO: 15, or a truncated amino acid sequence of any one
of SEQ ID NO: 7 to SEQ ID NO: 15, wherein the amino acid sequence
comprises one or more amino acid substitutions such as from 1 to 5
amino acid substitutions.
IL-2R.alpha. ligands provided by the present disclosure can
comprise the amino acid sequence of Formula (3a) (SEQ ID NO: 16),
the amino acid sequence of Formula (3b) (SEQ ID NO: 17), or the
amino acid sequence of Formula (3c) (SEQ ID NO: 18):
--X.sup.5--X.sup.6--X.sup.7--X.sup.8-- (3a)
--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--C--X.sup.10--
(3b)
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.s-
up.8--X.sup.9--X.sup.10--X.sup.11--X.sup.12-- (3c)
wherein, X.sup.1 can be selected from an amino acid comprising a
large hydrophobic side chain; X.sup.2 can be selected from an amino
acid comprising a large hydrophobic side chain; X.sup.3 can be
selected from an amino acid; X.sup.4 can be C; X.sup.5 can be
selected from an amino acid comprising a small hydrophobic side
chain; X.sup.6 can be selected from an amino acid; X.sup.7 can be
selected from an amino acid; X.sup.8 can be selected from amino
acid comprising a small hydrophobic side chain; X.sup.9 can be C;
X.sup.10 can be selected from an amino acid comprising a basic side
chain or a polar/neutral side chain; X.sup.11 can be selected from
an amino acid comprising a small hydrophobic side chain; and
X.sup.12 can be selected from an amino acid.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.1 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.2 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.3 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.4 can be C.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.5 can be
selected from A, G, P, S, and T.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.6 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.7 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.8 can be
selected from A, G, P, S, and T.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.9 can be C.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.10 can be
selected from H, K, N, Q, R, S, T, and Y.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.11 can be
selected from A, G, P, S, and T.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.12 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.1 can be
selected from Y and W.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.2 can be V.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.3 can be
selected from M and I.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.4 can be C.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.5 can be S.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.6 can be A.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.7 can be F, L,
V, and M.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.8 can be G.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.9 can be C.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.10 can be
selected from K and R.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.11 can be
selected from S, P, and A.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.12 can be
selected from I, L, M, F, and W.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.1 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.2 can be V.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.3 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.4 can be C.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.5 can be G.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.6 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.7 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.8 can be G.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.9 can be C.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.10 can be
R.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.11 can be
S.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.12 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.12 can be
V.
In IL-2R.alpha. ligands of Formula (3a)-(3c), X.sup.2 can be V,
X.sup.4 can be C, X.sup.5 can be G, X.sup.8 can be G, X.sup.9 can
be C, X.sup.10 can be R, and X.sup.11 can be S.
In IL-2R.alpha. ligands of Formula (3a)-(3c),
X.sup.1 can be selected from F, I, L, M, V, W, and Y;
X.sup.2 can be V;
X.sup.3 can be selected from F, I, L, M, V, W, and Y;
X.sup.4 can be C;
X.sup.5 can be G;
X.sup.6 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.7 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.8 can be G;
X.sup.9 can be C;
X.sup.10 can be R;
X.sup.11 can be S; and
X.sup.12 can be selected from F, I, L, M, V, W, and Y.
IL-2R.alpha. ligands provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
19 to SEQ ID NO: 24:
TABLE-US-00007 SEQ ID NO: 19 F V L C G L Q G C R G S SEQ ID NO: 20
K V I C G W D G C R SEQ ID NO: 21 L V F C G K N G C H S G SEQ ID
NO: 22 V V L C T P K G C R S A SEQ ID NO: 23 Y V M C S A F G C K S
I SEQ ID NO: 24 F V H C T L L G C W S G
An IL-2R.alpha. ligand provided by the present disclosure can
comprise a truncated amino acid sequence of any one of SEQ ID NO:
16 to SEQ ID NO: 24.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
16 to SEQ ID NO: 24, or a truncated amino acid sequence of any one
of SEQ ID NO: 16 to SEQ ID NO: 24, wherein the amino acid sequence
can independently comprise from 1 to 4 glycines (G) (SEQ ID NO:
1041) on the N-terminus, on the C-terminus, or on both the N- and
C-termini.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
16 to SEQ ID NO: 24, or a truncated amino acid sequence of any one
of SEQ ID NO: 16 to SEQ ID NO: 24, wherein the amino acid sequence
comprises one or more amino acid substitutions such as from 1 to 5
amino acid substitutions.
IL-2R.alpha. ligands provided by the present disclosure can
comprise the amino acid sequence of Formula (4a) (SEQ ID NO: 25),
the amino acid sequence of Formula (4b) (SEQ ID NO: 26), the amino
acid sequence of Formula (4c) (SEQ ID NO: 27), or the amino acid
sequence of Formula (4d) (SEQ ID NO: 28):
--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9-- (4a)
--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--C--X.sup.10--
(4b)
--X.sup.2--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--C--X.sup.10--X-
.sup.11-- (4c)
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12-- (4d)
wherein, X.sup.1 can be selected from an amino acid comprising a
large hydrophobic side chain; X.sup.2 can be selected from an amino
acid comprising a large hydrophobic side chain; X.sup.3 can be
selected from an amino acid comprising a large hydrophobic side
chain; X.sup.4 can be C; X.sup.5 can be selected from an amino acid
comprising a small hydrophobic side chain; X.sup.6 can be selected
from an amino acid comprising a small hydrophobic side chain;
X.sup.7 can be selected from an amino acid comprising a large
hydrophobic side chain; X.sup.8 can be selected from an amino acid
comprising a small hydrophobic side chain; X.sup.9 can be C;
X.sup.10 can be selected from an amino acid comprising a basic side
chain; X.sup.11 can be selected from an amino acid comprising a
small hydrophobic side chain; and X.sup.12 can be selected from an
amino acid comprising a large hydrophobic side chain.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.1 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.2 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.3 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.4 can be C.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.5 can be
selected from A, G, P, S, and T.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.6 can be
selected from A, G, P, S, and T.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.7 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.8 can be
selected from A, G, P, S, and T.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.9 can be C.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.10 can be
selected from H, K, and R.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.11 can be
selected from A, G, P, S, and T.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.12 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.1 can be
selected from Y and W.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.2 can be V.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.3 can be
selected from M and I.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.4 can be C.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.5 can be S.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.6 can be A.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.7 can be
selected from F, L, V, and M.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.8 can be G.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.9 can be C.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.10 can be
selected from R and K.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.11 can be
selected from S, P, and A.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.12 can be
selected from I, M, F, and W.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.1 can be W.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.2 can be V.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.3 can be I.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.4 can be C.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.5 can be S.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.6 can be A.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.7 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.8 can be G.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.9 can be C.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.10 can be
R.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.11 can be
S.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.12 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (4a)-(4d), X.sup.1 can be W,
X.sup.2 can be V, X.sup.3 can be I, X.sup.4 can be C, X.sup.5 can
be S, X.sup.6 can be A, X.sup.8 can be G, X.sup.9 can be C,
X.sup.10 can be R, and X.sup.11 can be S.
In IL-2R.alpha. ligands of Formula (4a)-(4d),
X.sup.1 can be W;
X.sup.2 can be V;
X.sup.3 can be I;
X.sup.4 can be C;
X.sup.5 can be S;
X.sup.6 can be A;
X.sup.7 can be selected from F, I, L, M, V, W, and Y.
X.sup.8 can be G;
X.sup.9 can be C;
X.sup.10 can be selected from R and K;
X.sup.11 can be S; and
X.sup.12 can be selected from F, I, L, M, V, W, and Y.
IL-2R.alpha. ligands provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
29 to SEQ ID NO: 36:
TABLE-US-00008 SEQ ID NO: 29 W V I C S A L G C R S L SEQ ID NO: 30
W V I C S A L G C R S M SEQ ID NO: 31 W V I C S A V G C R P F SEQ
ID NO: 32 W V I C S A M G C R S I SEQ ID NO: 33 W V I C S A L G C R
S I SEQ ID NO: 34 W V I C S A F G C R S M SEQ ID NO: 35 W V I C S A
L G C R P F SEQ ID NO: 36 W V I C S A L G C K A W
An IL-2R.alpha. ligand provided by the present disclosure can
comprise a truncated amino acid sequence of any one of SEQ ID NO:
25 to SEQ ID NO: 36.
An IL-2R.alpha. ligand.dagger.s provided by the present disclosure
can comprise an amino acid sequence selected from any one of SEQ ID
NO: 25 to SEQ ID NO: 36, or a truncated amino acid sequence of any
one of SEQ ID NO: 25 to SEQ ID NO: 36, wherein the amino acid
sequence can independently comprise from 1 to 4 glycines (G) (SEQ
ID NO: 1041) on the N-terminus, on the C-terminus, or on both the
N- and C-termini.
An IL-2R.alpha. ligand.dagger.s provided by the present disclosure
can comprise an amino acid sequence selected from any one of SEQ ID
NO: 25 to SEQ ID NO: 36, or a truncated amino acid sequence of any
one of SEQ ID NO: 25 to SEQ ID NO: 36, wherein the amino acid
sequence comprises one or more amino acid substitutions such as
from 1 to 5 amino acid substitutions.
IL-2R.alpha. ligands provided by the present disclosure can
comprise the amino acid sequence of Formula (5a) (SEQ ID NO: 37),
the amino acid sequence of Formula (5b) (SEQ ID NO: 38), the amino
acid sequence of Formula (5c) (SEQ ID NO: 39), or the amino acid
sequence of Formula (5d) (SEQ ID NO: 40):
--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9-- (5a)
--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--C--X.sup.11--
(5b)
--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--C--X.sup.-
11--X.sup.12-- (5c)
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12-- (5d)
wherein, X.sup.1 can be selected from an amino acid comprising an
aromatic side chain or a large hydrophobic side chain; X.sup.2 can
be selected from an amino acid comprising a large hydrophobic side
chain; X.sup.3 can be selected from an amino acid comprising a
large hydrophobic side chain; X.sup.4 can be C; X.sup.5 can be
selected from an amino acid comprising a small hydrophobic side
chain or an acidic side chain; X.sup.6 can be selected from an
amino acid; X.sup.7 can be selected from an amino acid; X.sup.8 can
be selected from an amino acid; X.sup.9 can be selected from an
amino acid comprising a small hydrophobic side chain; X.sup.10 can
be C; X.sup.11 can be selected from an amino acid comprising a
basic side chain; and X.sup.12 can be selected from an amino
acid.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.1 can be
selected from F, H, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.2 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.3 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.4 can be C.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.5 can be
selected from A, G, H, K, P, R, S, and T.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.6 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.7 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.8 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.9 can be
selected from A, G, P, S, and T.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.10 can be
C.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.11 can be
selected from H, K, and R.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.12 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.1 can be
selected from F, H, W, and Y.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.2 can be V.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.3 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.4 can be
selected from F, K, L, V, W, and H.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.5 can be V.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.5 can be
selected from L, F, M, H, T, A, and I.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.5 can be C.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.6 can be
selected from G, T, S, R, and K.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.6 can be
selected from L, W, K, P, A, N, W, and V,
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.7 can be
selected from Q, D, N, K, F, L, R, G, and D.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.8 can be
selected from G, N, Y, H, and G.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.9 can be G.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.10 can be
C.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.11 can be
selected from G, S, R, T, and Y.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.12 can be
selected from S, G, A, I, G, P, R, and S.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.1 can be
selected from F, W, and Y.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.2 can be V.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.3 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.4 can be C.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.5 can be
selected from A, G, P, S, and T.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.5 can be
selected from H, K, and R.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.5 can be S.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.6 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.6 can be W.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.7 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.8 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.9 can be G.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.10 can be
C.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.11 can be
R.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.12 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (5a)-(5d), X.sup.2 can be V,
X.sup.4 can be C, X.sup.5 can be S, X.sup.9 can be G, X.sup.10 can
be C, and X.sup.11 can be R.
In IL-2R.alpha. ligands of Formula (5a)-(5d),
X.sup.1 can be selected from F, H, I, L, M, V, W, and Y;
X.sup.2 can be V;
X.sup.3 can be selected from F, I, L, M, V, W, and Y;
X.sup.4 can be C;
X.sup.5 can be S;
X.sup.6 can be selected from F, I, L, M, V, W, and Y;
X.sup.7 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.8 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.9 can be G;
X.sup.10 can be C;
X.sup.11 can be R; and
X.sup.12 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y.
IL-2R.alpha. ligands provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
41 to SEQ ID NO: 45:
TABLE-US-00009 SEQ ID NO: 41 Y V L C S N R N G C R P SEQ ID NO: 42
Y V T C R W G Y G C T R SEQ ID NO: 43 W V A C S W D H G C R S SEQ
ID NO: 44 H V I C S V N G G C R G SEQ ID NO: 45 W V X C K P L H G C
Y G
An IL-2R.alpha. ligand provided by the present disclosure can
comprise a truncated amino acid sequence of any one of SEQ ID NO:
37 to SEQ ID NO: 45.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
37 to SEQ ID NO: 45, or a truncated amino acid sequence of any one
of SEQ ID NO: 37 to SEQ ID NO: 45, wherein the amino acid sequence
can independently comprise from 1 to 4 glycines (G) (SEQ ID NO:
1041) on the N-terminus, on the C-terminus, or on both the N- and
C-termini.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
37 to SEQ ID NO: 45, or a truncated amino acid sequence of any one
of SEQ ID NO: 37 to SEQ ID NO: 45, wherein the amino acid sequence
comprises one or more amino acid substitutions such as from 1 to 5
amino acid substitutions.
IL-2R.alpha. ligands provided by the present disclosure can
comprise the amino acid sequence of Formula (6a) (SEQ ID NO: 46),
the amino acid sequence of Formula (6b) (SEQ ID NO: 47), the amino
acid sequence of Formula (6c) (SEQ ID NO: 48), or the amino acid
sequence of Formula (6d) (SEQ ID NO: 49):
--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.sup.11--
(6a)
--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.100--X.s-
up.11--C--X.sup.13-- (6b)
--X.sup.2--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup-
.10--X.sup.11--C--X.sup.13--X.sup.14-- (6c)
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12--X.sup.13--X.sup.14--X.sup.15--
(6d)
wherein, X.sup.1 can be selected from an amino acid; X.sup.2 can be
selected from an amino acid; X.sup.3 can be selected from an amino
acid comprising a large hydrophobic side chain or an aromatic side
chain; X.sup.4 can be C; X.sup.5 can be selected from an amino acid
comprising a large hydrophobic side chain; X.sup.6 can be selected
from an amino acid comprising a basic side chain; X.sup.7 can be
selected from an amino acid comprising a small hydrophobic side
chain or a polar neutral side chain; X.sup.8 can be selected from
an amino acid comprising an acidic side chain; X.sup.9 can be
selected from an amino acid comprising a small hydrophobic side
chain; X.sup.10 can be selected from an amino acid; X.sup.11 can be
selected from an amino acid comprising a small hydrophobic side
chain; X.sup.12 can be C; X.sup.13 can be selected from an amino
acid comprising an aromatic side chain or a large hydrophobic side
chain; X.sup.14 can be selected from an amino acid comprising a
small hydrophobic side chain or a polar neutral side chain; and
X.sup.15 can be selected from an amino acid.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.1 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y; X.sup.2 can be selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y; X.sup.3 can be selected from F, H,
I, L, M, V, W, and Y; X.sup.4 can be C; X.sup.5 can be selected
from F, I, L, M, V, W, and Y; X.sup.6 can be selected from H, K,
and R; X.sup.7 can be selected from A, G, H, N, P, Q, S, T, and Y;
X.sup.8 can be selected from D and E; X.sup.9 can be selected from
A, G, P, S, and T; X.sup.10 can be selected from A, D, E, F, G, H,
I, K, L, M, N, P, Q, R, S, T, V, W, and Y; X.sup.11 can be selected
from A, G, P, S, and T; X.sup.12 can be C; X.sup.13 can be selected
from F, H, I, L, M, V, W, and Y; X.sup.14 can be selected from A,
G, H, N, P, Q, S, T, and Y; and X.sup.1 can be selected from any A,
D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.1 can be
selected from E, K, R, T, and L.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.2 can be
selected from Q, Y, V, K, and R.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.3 can be
selected from F, W, V, and L.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.4 can be C.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.5 can be L.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.6 can be
selected from V, R, A, and K.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.7 can be S.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.8 can be
selected from D and E.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.9 can be P.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.10 can be
selected from M, D, N, M Q, and T.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.11 can be
selected from A and S.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.12 can be
selected from C.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.13 can be
selected from F and W.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.14 can be
selected from S, A, and I.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.15 can be
selected from L, T, M, and V.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.1 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.2 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.3 can be
selected from F, W, and Y.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.4 can be C.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.5 can be L.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.6 can be
selected from H, K, and R.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.7 can be S.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.8 can be
selected from D and E.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.9 can be P.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.10 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.11 can be
A.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.12 can be
C.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.13 can be
selected from F, W, and Y.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.13 can be
W.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.14 can be
S.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.15 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (6a)-(6d), X.sup.4 can be C,
X.sup.5 can be L, X.sup.7 can be S, X.sup.8 can be E, X.sup.9 can
be P, X.sup.11 can be A, X.sup.12 can be C, X.sup.12 can be W, and
X.sup.14 can be S.
In IL-2R.alpha. ligands of Formula (6a)-(6d),
X.sup.1 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.2 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.3 can be selected from F, H, I, L, M, V, W, and Y;
X.sup.4 can be C;
X.sup.5 can be L;
X.sup.6 can be selected from H, K, and R;
X.sup.7 can be S;
X.sup.8 can be E;
X.sup.9 can be P;
X.sup.10 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.11 can be A;
X.sup.12 can be C;
X.sup.13 can be W;
X.sup.14 can be S; and
X.sup.15 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y.
IL-2R.alpha. ligands provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
50 to SEQ ID NO: 54:
TABLE-US-00010 SEQ ID NO: 50 E Q F C LV S D P M A C WS L SEQ ID NO:
51 K Y W C L R S E P D A C F A T SEQ ID NO: 52 R V Y C L A S E P N
S C W S T SEQ ID NO: 53 T K L C L K S E P Q A C W S M SEQ ID NO: 54
I R F C L R S E P T A C W I V
An IL-2R.alpha. ligand provided by the present disclosure can
comprise a truncated amino acid sequence of any one of SEQ ID NO:
46 to SEQ ID NO: 54.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
46 to SEQ ID NO: 54, or a truncated amino acid sequence of any one
of SEQ ID NO: 46 to SEQ ID NO: 54, wherein the amino acid sequence
can independently comprise from 1 to 4 glycines (G) (SEQ ID NO:
1041) on the N-terminus, on the C-terminus, or on both the N- and
C-termini.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
46 to SEQ ID NO: 54, or a truncated amino acid sequence of any one
of SEQ ID NO: 46 to SEQ ID NO: 54, wherein the amino acid sequence
comprises one or more amino acid substitutions such as from 1 to 5
amino acid substitutions.
IL-2R.alpha. ligands provided by the present disclosure can
comprise the amino acid sequence of Formula (7a) (SEQ ID NO: 55),
the amino acid sequence of Formula (7b) (SEQ ID NO: 56), the amino
acid sequence of Formula (7c) (SEQ ID NO: 57), or the amino acid
sequence of Formula (7d) (SEQ ID NO: 58):
--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.sup.11--
(7a)
--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.su-
p.11--C--X.sup.13-- (7b)
--X.sup.2--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup-
.10--X.sup.11--C--X.sup.13--X.sup.14-- (7c)
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12--X.sup.13--X.sup.14--X.sup.15--
(7d)
wherein, X.sup.1 can be selected from a basic amino acid; X.sup.2
can be selected from a basic amino acid; X.sup.3 can be selected
from an amino acid comprising a large hydrophobic side chain;
X.sup.4 can be C; X.sup.5 can be selected from an amino acid
comprising a large hydrophobic side chain; X.sup.6 can be selected
from an amino acid comprising a basic side chain; X.sup.7 can be
selected from an amino acid comprising a small hydrophobic side
chain or a polar neutral side chain; X.sup.8 can be selected from
an amino acid comprising a large hydrophobic side chain; X.sup.9
can be selected from an amino acid comprising a small hydrophobic
side chain; X.sup.10 can be selected from an amino acid comprising
a small hydrophobic side chain or a polar neutral side chain;
X.sup.11 can be selected from an amino acid comprising a small
hydrophobic side chain; X.sup.12 can be C; X.sup.13 can be selected
from an amino acid comprising an aromatic side chain or a large
hydrophobic side chain; X.sup.14 can be selected from an amino acid
comprising a small hydrophobic side chain or a polar neutral side
chain; and X.sup.15 can be selected from an amino acid comprising a
large hydrophobic side chain.
In IL-2R.alpha. ligands of Formula (7a)-(7d),
X.sup.1 can be selected from K, and R;
X.sup.2 can be selected from H, K, and R;
X.sup.3 can be selected from F, I, L, M, V, W, and Y;
X.sup.4 can be C;
X.sup.5 can be selected from F, I, L, M, V, W, and Y;
X.sup.6 can be selected from H, K, and R;
X.sup.7 can be selected from A, G, H, N, P, Q, S, T, and Y;
X.sup.8 can be selected from F, I, L, M, V, W, and Y;
X.sup.9 can be selected from A, G, P, S, and T;
X.sup.10 can be selected from A, G, H, N, P, Q, S, T, and Y;
X.sup.11 can be selected from A, G, P, S, and T;
X.sup.12 can be C;
X.sup.13 can be selected from F, H, I, L, M, V, W, and Y;
X.sup.14 can be selected from A, G, H, N, P, Q, S, T, and Y;
and
X.sup.15 can be selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.1 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.2 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.3 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.4 can be C.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.5 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.5 can be L.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.6 can be
selected from H, K, and R.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.7 can be
selected from A, G, P, S, and T.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.7 can be
selected from H, N, Q, S, T, and Y.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.7 can be S.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.8 can be
selected from D and E.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.9 can be P.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.10 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.11 can be
A.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.12 can be
C.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.13 can be
W.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.14 can be
S.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.15 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.1 can be R.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.2 can be R.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.3 can be F.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.4 can be C.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.5 can be L.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.6 can be R.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.7 can be S.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.8 can be E.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.9 can be P.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.10 can be
T.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.11 can be
A.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.12 can be
C.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.13 can be
W.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.14 can be
T.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.15 can be
V.
In IL-2R.alpha. ligands of Formula (7a)-(7d), X.sup.1 can be R,
X.sup.2 can be R, X.sup.3 can be F, X.sup.4 can be C, X.sup.5 can
be L, X.sup.6, can be R, X.sup.7 can be S, X.sup.8 can be E,
X.sup.9 can be P, X.sup.10 can be T, X.sup.11 can be A, X.sup.12
can be C, X.sup.13 can be W, and X.sup.15 can be V.
In IL-2R.alpha. ligands of Formula (7a)-(7d),
X.sup.1 can be selected from K and R;
X.sup.2 can be R;
X.sup.3 can be F;
X.sup.4 can be C;
X.sup.5 can be L;
X.sup.6 can be R;
X.sup.7 can be S;
X.sup.8 can be E;
X.sup.9 can be P;
X.sup.10 can be T;
X.sup.11 can be A;
X.sup.12 can be C;
X.sup.13 can be W;
X.sup.14 can be T; and
X.sup.15 can be V.
IL-2R.alpha. ligands provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
59 to SEQ ID NO: 68:
TABLE-US-00011 SEQ ID NO: 59 R R F C L R S E P T A C W I V SEQ ID
NO: 60 K L F C L R S G D R A C W V V SEQ ID NO: 61 M R F C L R S E
P T A C W T V SEQ ID NO: 62 R R F C L R S E P T A C W D V SEQ ID
NO: 63 R R F C L R S D P T A C W I V SEQ ID NO: 64 K R F C L R S E
P T A C W T V SEQ ID NO: 65 R R F C L R S E P M A C W T V SEQ ID
NO: 66 R R F C L R S E P T A C W T V SEQ ID NO: 67 R R F C L R S E
P AA C W F V SEQ ID NO: 68 R R F C L R S E P T A C W Y V
An IL-2R.alpha. ligand provided by the present disclosure can
comprise a truncated amino acid sequence of any one of SEQ ID NO:
55 to SEQ ID NO: 68.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
55 to SEQ ID NO: 68, or a truncated amino acid sequence of any one
of SEQ ID NO: 55 to SEQ ID NO: 68, wherein the amino acid sequence
can independently comprise from 1 to 4 glycines (G) (SEQ ID NO:
1041) on the N-terminus, on the C-terminus, or on both the N- and
C-termini.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
55 to SEQ ID NO: 68, or a truncated amino acid sequence of any one
of SEQ ID NO: 55 to SEQ ID NO: 68, wherein the amino acid sequence
comprises one or more amino acid substitutions such as from 1 to 5
amino acid substitutions.
IL-2R.alpha. ligands provided by the present disclosure can
comprise the amino acid sequence of Formula (8a) (SEQ ID NO: 69)
the amino acid sequence of Formula (8b) (SEQ ID NO: 70), or the
amino acid sequence of Formula (8c) (SEQ ID NO: 71):
--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.sup.1-
1-- (8a)
--X.sup.2--C--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup-
.9--X.sup.10--X.sup.11--C--X.sup.13-- (8b)
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12--X.sup.13--X.sup.14--
(8c)
wherein, X.sup.1 can be selected from an amino acid; X.sup.2 can be
selected from an amino acid comprising a basic side chain; X.sup.3
can be C; X.sup.4 can be selected from an amino acid comprising a
large hydrophobic side chain or a basic side chain; X.sup.5 can be
selected from an amino acid; X.sup.6 can be selected from an amino
acid comprising an acidic side chain; X.sup.7 can be selected from
an amino acid; X.sup.8 can be selected from an amino acid; X.sup.9
can be selected from an amino acid; X.sup.10 can be selected from
an amino acid comprising a small hydrophobic side chain; X.sup.11
can be selected from an amino acid; X.sup.12 can be C; X.sup.13 can
be selected from an amino acid comprising a large hydrophobic side
chain; and X.sup.14 can be selected from an amino acid comprising a
large hydrophobic side chain.
In IL-2R.alpha. ligands of Formula (8a)-(8c),
X.sup.1 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.2 can be selected from H, K, and R;
X.sup.3 can be C;
X.sup.4 can be selected from F, H, I, K, L, M, R, V, W, and Y;
X.sup.5 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.6 can be selected from D and E;
X.sup.7 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.8 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.9 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.10 can be selected from A, G, P, S, and T;
X.sup.11 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.12 can be C;
X.sup.13 can be selected from F, I, L, M, V, W, and Y; and
X.sup.14 can be selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.1 can be
selected from R, I, L, M, N, S, T, V, and D.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.2 can be
selected from S, K, R, H, G, and F.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.3 can be C.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.4 can be
selected from N, R, I, T, V, L, and D.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.5 can be
selected from R, V, L, M, V, G, Y, I, F, and T.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.5 can be
selected from Y, L, E, D, S, I, Y, D, and R.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.6 can be
selected from Y, L, E, D, S, and R.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.7 can be
selected from G, E, K, T, P, W, L, Y, G, S, and R.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.8 can be
selected from I, A, Q, R, S R, L, N, P, A, I, R, D, and W.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.9 can be
selected from W, G, S, D, R, L, F, P, A, and T.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.10 can be
selected from G, T, E, W, Q, R, and Y.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.11 can be
selected from H, P, I, T, H, A, S, F, and Y.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.12 can be
C.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.13 can be
selected from D, V, L, I, Y, I, R, H, T, I, and W.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.14 can be
selected from T, S, F, and I.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.1 can be
selected from R, I, L, M, N, S, T, V, and D.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.2 can be
selected from S, K, R, H, G, and F.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.3 can be C.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.4 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.4 can be
selected from H, K, and R.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.5 can be
selected from Y, L, E, D, S, I, Y, D, and R.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.6 can be
selected from Y, L, E, D, S, and R.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.6 can be
selected from D and E.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.7 can be
selected from G, E, K, T, P, W, L, Y, G, S, and R.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.8 can be
selected from I, A, Q, R, S R, L, N, P, A, I, R, D, and W.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.9 can be
selected from W, G, S, D, R, L, F, P, A, and T.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.10 can be
selected from G, T, E, W, Q, R, and Y.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.10 can be
G.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.11 can be
selected from H, P, I, T, H, A, S, F, and Y.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.12 can be
C.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.13 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.14 can be
F.
In IL-2R.alpha. ligands of Formula (8a)-(8c), X.sup.2 can be R,
X.sup.3 can be C, X.sup.6, can be D, X.sup.10 can be G, X.sup.12
can be C, and X.sup.14 can be F.
In IL-2R.alpha. ligands of Formula (8a)-(8c),
X.sup.1 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.2 can be R;
X.sup.3 can be C;
X.sup.4 can be selected from F, H, I, K, L, M, R, V, W, and Y;
X.sup.5 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.6 can be D;
X.sup.7 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.8 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.9 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.10 can be G;
X.sup.11 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.12 can be C;
X.sup.13 can be selected from F, I, L, M, V, W, and Y; and
X.sup.14 can be F.
IL-2R.alpha. ligands provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
72 to SEQ ID NO: 86:
TABLE-US-00012 SEQ ID NO: 72 R S C N R Y G I W G H C D T SEQ ID NO:
73 I K C R V L E A G T P C V F SEQ ID NO: 74 I R C R Y E K Q S G I
C L F SEQ ID NO: 75 L R C R L D T R D G T C R F SEQ ID NO: 76 M R C
I L S P S R E H C L F SEQ ID NO: 77 N H C T M D W R L G A C I F SEQ
ID NO: 78 S G C R L S L L D G H C Y F SEQ ID NO: 79 S K C V Y D Y N
F G T C I F SEQ ID NO: 80 S R C V M S L Q L G A C I F SEQ ID NO: 81
T R C T V I G P P W S C R F SEQ ID NO: 82 V F C I G Y G A A Q S C H
S SEQ ID NO: 83 V R C L Y D S I T R T C T F SEQ ID NO: 84 V S C K I
D R R S G S C L F SEQ ID NO: 85 V S C R F R P D L G F C I F SEQ ID
NO: 86 D R C D T R T W G Y Y C W I
An IL-2R.alpha. ligand provided by the present disclosure can
comprise a truncated amino acid sequence of any one of SEQ ID NO:
69 to SEQ ID NO: 86.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
69 to SEQ ID NO: 86, or a truncated amino acid sequence of any one
of SEQ ID NO: 69 to SEQ ID NO: 86, wherein the amino acid sequence
can independently comprise from 1 to 4 glycines (G) (SEQ ID NO:
1041) on the N-terminus, on the C-terminus, or on both the N- and
C-termini.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
69 to SEQ ID NO: 86, or a truncated amino acid sequence of any one
of SEQ ID NO: 69 to SEQ ID NO: 86, wherein the amino acid sequence
comprises one or more amino acid substitutions such as from 1 to 5
amino acid substitutions.
IL-2R.alpha. ligands provided by the present disclosure can
comprise the amino acid sequence of Formula (9a) (SEQ ID NO: 87),
the amino acid sequence of Formula (9b) (SEQ ID NO: 88), the amino
acid sequence of Formula (9c) (SEQ ID NO: 89), or the amino acid
sequence of Formula (9d) (SEQ ID NO: 90):
--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.sup.11--X.sup.-
12-- (9a)
--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.su-
p.10--X.sup.11--X.sup.12--C--X.sup.14-- (9b)
--X.sup.2--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup-
.10--X.sup.11--X.sup.12--C--X.sup.14--X.sup.15-- (9c)
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12--X.sup.13--X.sup.14--X.sup.15--X.su-
p.16-- (9d)
wherein, X.sup.1 can be selected from an amino acid; X.sup.2 can be
selected from an amino acid comprising a large hydrophobic side
chain; X.sup.3 can be selected from an amino acid comprising a
large hydrophobic side chain or an acidic side chain; X.sup.4 can
be C; X.sup.5 can be selected from an amino acid comprising a large
hydrophobic side chain or a basic side chain; X.sup.6 can be
selected from an amino acid comprising a large hydrophobic side
chain; X.sup.7 can be selected from an amino acid; X.sup.8 can be
selected from an amino acid comprising a small hydrophobic side
chain; X.sup.9 can be selected from an amino acid comprising a
small hydrophobic side chain; X.sup.10 can be selected from an
amino acid comprising a large hydrophobic side chain or a basic
side chain; X.sup.11 can be selected from an amino acid comprising
a basic side chain or an acidic side chain; X.sup.12 can be
selected from an amino acid comprising a small hydrophobic side
chain or a polar neutral side chain; X.sup.13 can be C; X.sup.14
can be selected from an amino acid; X.sup.15 can be selected from
an amino acid; and X.sup.16 can be selected from an amino acid.
In IL-2R.alpha. ligands of Formula (9a)-(9d),
X.sup.1 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.2 can be selected from F, I, L, M, V, W, and Y;
X.sup.3 can be selected from D, E, F, I, L, M, V, W, and Y;
X.sup.4 can be C;
X.sup.5 can be selected from F, H, I, K, L, M, R, V, W, and Y;
X.sup.6 can be selected from F, I, L, M, V, W, and Y;
X.sup.7 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.8 can be selected from A, G, P, S, and T;
X.sup.9 can be selected from A, G, P, S, and T;
X.sup.10 can be selected from F, H, I, K, L, M, R, V, W, and Y;
X.sup.11 can be selected from D, E, H, K, and R;
X.sup.12 can be selected from A, G, H, N, P, Q, S, T, and Y;
X.sup.13 can be C;
X.sup.14 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.15 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y; and
X.sup.16 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.1 can be
selected from G, E, F, K, P, Q, R, S, and V.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.2 can be
selected from S, W, I, F, L, and R.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.3 can be
selected from R, E, I, V, S, N, F, L, and M.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.4 can be C.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.5 can be
selected from Y, R, V, T, E, I, and K.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.6 can be
selected from W, F, Y, L, H, I, T, S, and V.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.7 can be
selected from D, L, S, D, V, Y, S, Q, I, R, M, G, and A.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.8 can be P.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.9 can be G.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.10 can be
selected from R, S, T, N, R, V, L, H, W, and Y.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.11 can be
selected from E, R, H, G, E, K, Q, and V.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.12 can be
selected from V, G, S, A, and W.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.13 can be
C.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.14 can be
selected from I, S, R, W, H, V, K, T, R, G, and P.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.13 can be
selected from F, L, M, S, W, T, A, and R.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.14 can be
selected from K, F, V, I, F, M, L, Q, T, and N.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.1 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.2 can be
selected from F, W, and Y.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.3 can be W.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.4 can be C.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.5 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.5 can be
selected from D and E.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.6 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.6 can be
selected from F, W, and Y.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.7 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.8 can be P.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.9 can be G.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.10 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.10 can be
selected from F, W, and Y.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.10 can be
selected from H, K, and R.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.11 can be
selected from H, K, and R.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.11 can be
selected from D and E.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.12 can be
selected from A, G, P, S, and T.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.12 can be
selected from N, Q, S, T, and Y.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.11 can be
C.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.14 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.15 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.16 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.16 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.16 can be
selected from F, W, and Y.
In IL-2R.alpha. ligands of Formula (9a)-(9d), X.sup.2 can be W,
X.sup.3 can be E, X.sup.4 can be C, X.sup.5, can be R, X.sup.8 can
be P, X.sup.9 can be G, X.sup.10 can be R, X.sup.11 can be R,
X.sup.12 can be G, and X.sup.11 can be C.
In IL-2R.alpha. ligands of Formula (9a)-(9d),
X.sup.1 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.2 can be W;
X.sup.3 can be E;
X.sup.4 can be C;
X.sup.5 can be R;
X.sup.6 can be selected from F, H, I, L, M, V, W, and Y;
X.sup.7 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.8 can be P;
X.sup.9 can be G
X.sup.10 can be R;
X.sup.11 can be R;
X.sup.12 can be G;
X.sup.13 can be C;
X.sup.14 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.15 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y; and
X.sup.16 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y.
IL-2R.alpha. ligands provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
91 to SEQ ID NO: 104:
TABLE-US-00013 SEQ ID NO: 91 G S R C Y W D P G R E V C I F K SEQ ID
NO: 92 E W E C R F L P G R R G C S L F SEQ ID NO: 93 F W E C V Y S
P G S R G C R M V SEQ ID NO: 94 G F R C T Y D P G T H S C W S I SEQ
ID NO: 95 K W I C R L V P G N G A C H S F SEQ ID NO: 96 P W V C E H
Y P G R R G C V L M SEQ ID NO: 97 Q W S C V F S P G V R G C K L V
SEQ ID NO: 98 R F I C R I Q P G R E G C W S L SEQ ID NO: 99 R W E C
I Y I P G R K G C T L Q SEQ ID NO: 100 S L N C K T R P G L R W C T
W T SEQ ID NO: 101 S W E C V Y M P G H Q G C L R F SEQ ID NO: 102 V
R F C R S G P G W V S C G T Q SEQ ID NO: 103 V R L C R V G P G Y E
S C P A N SEQ ID NO: 104 V R M C Y V A P G Y V S C P R M
An IL-2R.alpha. ligand provided by the present disclosure can
comprise a truncated amino acid sequence of any one of SEQ ID NO:
87 to SEQ ID NO: 104.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
87 to SEQ ID NO: 104, or a truncated amino acid sequence of any one
of SEQ ID NO: 87 to SEQ ID NO: 104, wherein the amino acid sequence
can independently comprise from 1 to 4 glycines (G) (SEQ ID NO:
1041) on the N-terminus, on the C-terminus, or on both the N- and
C-termini.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
87 to SEQ ID NO: 104, or a truncated amino acid sequence of any one
of SEQ ID NO: 87 to SEQ ID NO: 104, wherein the amino acid sequence
comprises one or more amino acid substitutions such as from 1 to 5
amino acid substitutions.
IL-2R.alpha. ligands provided by the present disclosure can
comprise the amino acid sequence of Formula (10a) (SEQ ID NO: 105),
the amino acid sequence of Formula (10b) (SEQ ID NO: 106), the
amino acid sequence of Formula (10c) (SEQ ID NO: 107), or the amino
acid sequence of Formula (10d) (SEQ ID NO: 108):
--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.sup.11--X.sup.-
12-- (10a)
--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.su-
p.11--X.sup.12--C--X.sup.14-- (10b)
--X.sup.2--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup-
.10--X.sup.11--X.sup.12--C--X.sup.14--X.sup.15-- (10c)
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12--X.sup.13--X.sup.14--X.sup.15--X.su-
p.16-- (10d)
wherein, X.sup.1 can be selected from an amino acid comprising an
acidic side chain; X.sup.2 can be selected from an amino acid
comprising a large hydrophobic side chain; X.sup.3 can be selected
from an amino acid comprising an acidic side chain; X.sup.4 can be
C; X.sup.5 can be selected from an amino acid comprising a large
hydrophobic side chain; X.sup.6 can be selected from an amino acid
comprising a large hydrophobic side chain; X.sup.7 can be selected
from an amino acid comprising a large hydrophobic side chain;
X.sup.8 can be selected from an amino acid comprising a small
hydrophobic side chain; X.sup.9 can be selected from an amino acid
comprising a small hydrophobic side chain; X.sup.10 can be selected
from an amino acid comprising a basic side chain; X.sup.11 can be
selected from an amino acid comprising a basic side chain; X.sup.12
can be selected from an amino acid comprising a small hydrophobic
side chain; X.sup.13 can be C; X.sup.14 can be selected from an
amino acid comprising a small hydrophobic side chain or a polar
neutral side chain; X.sup.15 can be selected from an amino acid
comprising a large hydrophobic side chain; and X.sup.16 can be
selected from an amino acid comprising a large hydrophobic side
chain.
In IL-2R.alpha. ligands of Formula (10a)-(10d),
X.sup.1 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.2 can be selected from F, I, L, M, V, W, and Y;
X.sup.3 can be selected from D and E;
X.sup.4 can be C;
X.sup.5 can be selected from F, I, L, M, V, W, and Y;
X.sup.6 can be selected from F, I, L, M, V, W, and Y;
X.sup.7 can be selected from F, I, L, M, V, W, and Y;
X.sup.8 can be selected from A, G, P, S, and T;
X.sup.9 can be selected from A, G, P, S, and T;
X.sup.10 can be selected from H, K, and R;
X.sup.11 can be selected from H, K, and R;
X.sup.12 can be selected from A, G, P, S, and T;
X.sup.13 can be C;
X.sup.14 can be selected from A, G, H, N, P, Q, S, T, and Y;
X.sup.15 can be selected from F, I, L, M, V, W, and Y; and
X.sup.16 can be selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.1 can be
selected from N, D, E, A, V, and T.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.2 can be
selected from W and Y.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.3 can be
selected from E, H, and D.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.4 can be
C.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.5 can be
selected from I, l, W, and V.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.6 can be
selected from F and I.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.7 can be
selected from S, L, and M.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.8 can be
P.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.9 can be
G.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.10 can be
selected from R and H.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.11 can be
selected from R and K.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.12 can be
G.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.13 can be
C.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.14 can be
selected from S, L, T, and F.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.13 can be
selected from L and G.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.14 can be
selected from F, M, T, and I.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.1 can be
selected from D and E.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.2 can be
W.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.3 can be
selected from D and E.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.4 can be
C.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.5 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.5 can be
selected from I and L.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.6 can be
F.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.7 can be
selected from L and M.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.8 can be
P.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.9 can be
G.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.10 can be
selected from H and R.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.11 can be
selected from K and R.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.12 can be
G.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.13 can be
C.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.14 can be
selected from S and T.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.15 can be
L.
In IL-2R.alpha. ligands of Formula (10a)-(10d), X.sup.16 can be
selected from F and M.
In IL-2R.alpha. ligands of Formula (10a)-(10d),
X.sup.1 can be D;
X.sup.2 can be W;
X.sup.3 can be E;
X.sup.4 can be C;
X.sup.5 can be L;
X.sup.6 can be F;
X.sup.7 can be L;
X.sup.8 can be P;
X.sup.9 can be G;
X.sup.10 can be selected from H and R;
X.sup.11 can be selected from K and R;
X.sup.12 can be G;
X.sup.13 can be C;
X.sup.14 can be T;
X.sup.15 can be L; and
X.sup.16 can be F.
IL-2R.alpha. ligands provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
109 to SEQ ID NO: 121:
TABLE-US-00014 SEQ ID NO: 109 N W E C I F S P G R R G C S L T SEQ
ID NO: 110 D W E C L F L P G R R G C L L F SEQ ID NO: 111 E W E C L
F M P G R R G C L L M SEQ ID NO: 112 A W E C L F L P G H R G C S L
F SEQ ID NO: 113 E W E C L F L P G R K G C T L F SEQ ID NO: 114 D W
E C I F L P G R R G C T L F SEQ ID NO: 115 V Y E C L F M P G R K G
CF G M SEQ ID NO: 116 E W E C W F L P G R R G C T L I SEQ ID NO:
117 D W H C L F L P G H R G C T L F SEQ ID NO: 118 D W E C L F L P
G R R G C T L F SEQ ID NO: 119 Y W E C V F M P G H R G C S L I SEQ
ID NO: 120 T W D C L F L P G R R G C T L M SEQ ID NO: 121 N W E C I
F S P G R R G C S L T
An IL-2R.alpha. ligand provided by the present disclosure can
comprise a truncated amino acid sequence of any one of SEQ ID NO:
105 to SEQ ID NO: 121.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
105 to SEQ ID NO: 121, or a truncated amino acid sequence of any
one of SEQ ID NO: 105 to SEQ ID NO: 121, wherein the amino acid
sequence can independently comprise from 1 to 4 glycines (G) (SEQ
ID NO: 1041) on the N-terminus, on the C-terminus, or on both the
N- and C-termini.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
105 to SEQ ID NO: 121, or a truncated amino acid sequence of any
one of SEQ ID NO: 105 to SEQ ID NO: 121, wherein the amino acid
sequence comprises one or more amino acid substitutions such as
from 1 to 5 amino acid substitutions.
IL-2R.alpha. ligands provided by the present disclosure can
comprise the amino acid sequence of Formula (11a) (SEQ ID NO: 122),
the amino acid sequence of Formula (11b) (SEQ ID NO: 123), the
amino acid sequence of Formula (11c) (SEQ ID NO: 124), or the amino
acid sequence of Formula (11d) (SEQ ID NO: 125):
--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.sup.11--X.sup.-
12-- (11a)
--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.su-
p.11--X.sup.12--C--X.sup.14-- (11b)
--X.sup.2--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup-
.10--X.sup.11--X.sup.12--C--X.sup.14--X.sup.15-- (11c)
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12--X.sup.13--X.sup.14--X.sup.15--X.su-
p.16-- (11d)
wherein, X.sup.1 can be selected from an amino acid; X.sup.2 can be
selected from an amino acid; X.sup.3 can be selected from an amino
acid; X.sup.4 can be C; X.sup.5 can be selected from an amino acid
comprising an acidic side chain; X.sup.6 can be selected from an
amino acid X.sup.7 can be selected from an amino acid comprising an
acidic side chain or an aromatic side chain; X.sup.8 can be
selected from an amino acid comprising a small hydrophobic side
chain; X.sup.9 can be selected from an amino acid comprising a
small hydrophobic side chain; X.sup.10 can be selected from an
amino acid comprising an aromatic chain; X.sup.11 can be selected
from an amino acid; X.sup.12 can be selected from an amino acid;
X.sup.13 can be C; X.sup.14 can be selected from an amino acid;
X.sup.15 can be selected from an amino acid comprising a large
hydrophobic side chain; and X.sup.16 can be selected from an amino
acid comprising a large hydrophobic side chain.
In IL-2R.alpha. ligands of Formula (11a)-(11d),
X.sup.1 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.2 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.3 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.4 can be C;
X.sup.5 can be selected from D and E;
X.sup.6 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.7 can be selected from D, E, F, H, W, and Y;
X.sup.8 can be selected from A, G, P, S, and T;
X.sup.9 can be selected from A, G, P, S, and T;
X.sup.10 can be selected from F, H, W, and Y;
X.sup.11 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.12 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.13 can be C;
X.sup.14 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.15 can be selected from F, I, L, M, V, W, and Y; and
X.sup.16 can be selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.1 can be
selected from A, E, F, G, K, R, T, Y, and W.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.2 can be
selected from G, T, K, Q, S, L, Q, R, and A.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.3 can be
selected from F, Y, W, and H.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.3 can be
selected from G, W, P, L, R, F, M, V, S, and P.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.4 can be
C.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.5 can be
selected from K, D, Y, T, Y, Q, F, L, and S.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.6 can be
selected from L, D, F, Y, W, N, D, M, V, D, L, and Y.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.7 can be
selected from N, H, F, D, N, S, L, and Y.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.8 can be
P.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.9 can be
G.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.10 can be
selected from T, H, L, S, Q, R, N, Y, W, V, S, and H.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.11 can be
selected from Q, W, P, D, E, S, P, E, H, G, R, and G.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.12 can be
selected from V, S, R, I, A, D, S, E, Y, and G.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.13 can be
C.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.14 can be
selected from S, E, T, V, I, D, Q, W, P, I, and Y.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.15 can be
selected from F, M, W, I, V, T, N, L, and S.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.16 can be
selected from Y, V, I, L, S, K, E, and R.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.4 can be
C.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.5 can be
D.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.7 can be
selected from D and H.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.8 can be
P.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.9 can be
G.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.10 can be
selected from F, H, W, and Y.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.13 can be
C.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.15 can be
selected from F, M, I, W, V, and L.
In IL-2R.alpha. ligands of Formula (11a)-(11d), X.sup.16 can be
selected from Y, V, I, and L.
In IL-2R.alpha. ligands of Formula (11a)-(11d),
X.sup.1 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.2 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.3 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.4 can be C;
X.sup.5 can be selected from D and E;
X.sup.6 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.7 can be selected from D, E, H, F, W, and Y;
X.sup.8 can be P;
X.sup.9 can be G;
X.sup.10 can be selected from H, F, W, and Y;
X.sup.11 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.12 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.13 can be C;
X.sup.14 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.15 can be selected from F, I, L, M, V, W, and Y; and
X.sup.16 can be selected from F, I, L, M, V, W, and Y.
IL-2R.alpha. ligands provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
126 to SEQ ID NO: 140:
TABLE-US-00015 SEQ ID NO: 126 A G W C K L N P G T Q V C S F Y SEQ
ID NO: 127 E T P C D L H P G H W S C S M V SEQ ID NO: 128 F F L C D
D F P G L P R C E W I SEQ ID NO: 129 G L R C Y F D P G S Q I C T F
L SEQ ID NO: 130 G Q R C T Y D P G Q D A C V F S SEQ ID NO: 131 G S
R C Y W D P G R E V C I I F SEQ ID NO: 132 K L W C Q N N P G N S I
C D M Y SEQ ID NO: 133 K S W C F D H P G Y P I C Q F Y SEQ ID NO:
134 R L F C L M N P G P P D C W I Y SEQ ID NO: 135 R Q F C L V S P
G Y E D C W F V SEQ ID NO: 136 T R M C F D D P G W H S C P V V SEQ
ID NO: 137 T R W C S L H P G V G E C V T L SEQ ID NO: 138 T T V C D
Y H P G S R Y C I N E SEQ ID NO: 139 Y A S C T Y L P G H R G C T L
V SEQ ID NO: 140 W L P C D D Y P G H G Y C Y S R
An IL-2R.alpha. ligand provided by the present disclosure can
comprise a truncated amino acid sequence of any one of SEQ ID NO:
122 to SEQ ID NO: 140.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
122 to SEQ ID NO: 140, or a truncated amino acid sequence of any
one of SEQ ID NO: 122 to SEQ ID NO: 140, wherein the amino acid
sequence can independently comprise from 1 to 4 glycines (G) (SEQ
ID NO: 1041) on the N-terminus, on the C-terminus, or on both the
N- and C-termini.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
122 to SEQ ID NO: 140, or a truncated amino acid sequence of any
one of SEQ ID NO: 122 to SEQ ID NO: 140, wherein the amino acid
sequence comprises one or more amino acid substitutions such as
from 1 to 5 amino acid substitutions.
IL-2R.alpha. ligands provided by the present disclosure can
comprise the amino acid sequence of Formula (12a) (SEQ ID NO: 141),
the amino acid sequence of Formula (12b) (SEQ ID NO: 142), or the
amino acid sequence of Formula (12c) (SEQ ID NO: 143):
--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.sup.1-
1--X.sup.12-- (12a)
--X.sup.2--C--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup-
.10--X.sup.11--X.sup.12--C--X.sup.14-- (12b)
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12--X.sup.13--X.sup.14--X.sup.15--X.su-
p.16-- (12c)
wherein, X.sup.1 can be selected from an amino acid; X.sup.2 can be
selected from an amino acid; X.sup.3 can be C; X.sup.4 can be
selected from an amino acid; X.sup.5 can be selected from an amino
acid comprising a large hydrophobic side chain; X.sup.6 can be
selected from an amino acid; X.sup.7 can be selected from an amino
acid; X.sup.8 can be selected from an amino acid; X.sup.9 can be
selected from an amino acid comprising an acidic side chain, a
small hydrophobic side chain, or a polar neutral side chain;
X.sup.10 can be selected from an amino acid; X.sup.11 can be
selected from an amino acid comprising a large hydrophobic side
chain; X.sup.12 can be selected from an amino acid comprising a
large hydrophobic side chain; X.sup.13 can be C; X.sup.14 can be
selected from an amino acid comprising a large hydrophobic side
chain; X.sup.15 can be selected from an amino acid comprising a
large hydrophobic side chain; and X.sup.16 can be selected from an
amino acid.
In IL-2R.alpha. ligands of Formula (12a)-(12c),
X.sup.1 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.2 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.3 can be C;
X.sup.4 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.5 can be selected from F, I, L, M, V, W, and Y;
X.sup.6 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.7 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.8 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.9 can be selected from A, D, E, G, H, N, P, Q, S, T, and
Y;
X.sup.10 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.11 can be selected from F, I, L, M, V, W, and Y;
X.sup.12 can be selected from F, I, L, M, V, W, and Y;
X.sup.13 can be C;
X.sup.14 can be selected from F, I, L, M, V, W, and Y; and
X.sup.15 can be selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.1 can be
selected from S, N, Q, R, and G.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.2 can be
selected from A, H, R, and G.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.3 can be
C.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.4 can be
selected from Q, T, N, M, and S.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.5 can be
selected from L and R.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.6 can be
selected from K, S, R, and V.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.7 can be
selected from W, K, and L.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.8 can be
selected from D, T, L, Q, and A.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.9 can be
selected from E, Y, D, and P.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.10 can be
selected from G, P, A, E, and S.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.11 can be
selected from W and L.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.12 can be
selected from T, V, I, and A.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.13 can be
C.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.14 can be
selected from L, V, Q, and I.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.13 can be
selected from F and A.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.1 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.2 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.3 can be
C.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.4 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.5 can be
L.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.6 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.7 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.8 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.9 can be
selected from D and E.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.10 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.11 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.11 can be
W.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.12 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.13 can be
C.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.14 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.15 can be
F.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.3 can be C,
X.sup.5 can be L, X.sup.9 can be D or E, X.sup.11 can be W,
X.sup.13 can be C, and X.sup.15 can be F.
In IL-2R.alpha. ligands of Formula (12a)-(12c),
X.sup.1 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.2 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.3 can be C;
X.sup.4 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.5 can be L;
X.sup.6 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.7 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.8 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.9 can be selected from D and E;
X.sup.10 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y:
X.sup.11 can be selected from F, I, L, M, V, W, and Y;
X.sup.12 can be selected from F, I, L, M, V, W, and Y;
X.sup.13 can be C;
X.sup.14 can be selected from F, I, L, M, V, W, and Y; and
X.sup.15 can be F.
In IL-2R.alpha. ligands of Formula (12a)-(12c), X.sup.3 can be C,
X.sup.5 can be L, X.sup.11 can be W, X.sup.13 can be C, and
X.sup.15 can be F.
IL-2R.alpha. ligands provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
144 to SEQ ID NO: 148:
TABLE-US-00016 SEQ ID NO: 144 S A C Q L K W D E G W T C L F SEQ ID
NO: 145 N H C T L S K T Y P W V C V F SEQ ID NO: 146 Q R C N R S L
L D A L I C Q A SEQ ID NO: 147 R G C M L R L Q P E L A C V F SEQ ID
NO: 148 G G C S L V W A D S W V C I F
An IL-2R.alpha. ligand provided by the present disclosure can
comprise a truncated amino acid sequence of any one of SEQ ID NO:
141 to SEQ ID NO: 148.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
141 to SEQ ID NO: 148, or a truncated amino acid sequence of any
one of SEQ ID NO: 141 to SEQ ID NO: 148, wherein the amino acid
sequence can independently comprise from 1 to 4 glycines (G) (SEQ
ID NO: 1041) on the N-terminus, on the C-terminus, or on both the
N- and C-termini.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
141 to SEQ ID NO: 148, or a truncated amino acid sequence of any
one of SEQ ID NO: 141 to SEQ ID NO: 148, wherein the amino acid
sequence comprises one or more amino acid substitutions such as
from 1 to 5 amino acid substitutions.
IL-2R.alpha. ligands provided by the present disclosure can
comprise the amino acid sequence of Formula (13a) (SEQ ID NO: 149),
the amino acid sequence of Formula (13b) (SEQ ID NO: 150), or the
amino acid sequence of Formula (13c) (SEQ ID NO: 151):
--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.sup.1-
1--X.sup.12-- (13a)
--X.sup.2--C--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup-
.10--X.sup.11--X.sup.12--C--X.sup.14-- (13b)
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12--X.sup.13--X.sup.14--X.sup.15--
(13c)
wherein, X.sup.1 can be selected from an amino acid comprising a
small hydrophobic side chain or a basic side chain; X.sup.2 can be
selected from an amino acid comprising a small hydrophobic side
chain or a basic side chain; X.sup.3 can be C; X.sup.4 can be
selected from an amino acid comprising a small hydrophobic side
chain; X.sup.5 can be selected from an amino acid comprising a
large hydrophobic side chain; X.sup.6 can be selected from an amino
acid comprising a large hydrophobic side chain; X.sup.7 can be
selected from an amino acid comprising a large hydrophobic side
chain; X.sup.8 can be selected from an amino acid; X.sup.9 can be
selected from an amino acid comprising an acidic side chain;
X.sup.10 can be selected from an amino acid comprising a small
hydrophobic side chain; X.sup.11 can be selected from an amino acid
comprising a large hydrophobic side chain; X.sup.12 can be selected
from an amino acid comprising a large hydrophobic side chain or an
acidic side chain; X.sup.13 can be C; X.sup.14 can be selected from
an amino acid comprising a large hydrophobic side chain; and
X.sup.15 can be selected from an amino acid comprising a large
hydrophobic side chain.
In IL-2R.alpha. ligands of Formula (13a)-(13c),
X.sup.1 can be selected from A, G, H, K, P, R, S, and T;
X.sup.2 can be selected from A, G, H, K, P, R, S, and T;
X.sup.3 can be C;
X.sup.4 can be selected from A, G, P, S, and T;
X.sup.5 can be selected from F, I, L, M, V, W, and Y;
X.sup.6 can be selected from F, I, L, M, V, W, and Y;
X.sup.7 can be selected from F, I, L, M, V, W, and Y;
X.sup.8 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.9 can be selected from D and E;
X.sup.10 can be selected from A, G, P, S, and T;
X.sup.11 can be selected from F, I, L, M, V, W, and Y;
X.sup.12 can be selected from D, E, F, I, L, M, V, W, and Y;
X.sup.13 can be C;
X.sup.14 can be selected from F, I, L, M, V, W, and Y; and
X.sup.15 can be selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.1 can be
selected from S, R, Q, V, A, and G.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.2 can be
selected from R, G, A, and S.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.3 can be
C.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.4 can be
selected from S, T, Q, and H.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.5 can be
L.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.6 can be
selected from V, Q, A, and R.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.7 can be
selected from W and F.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.8 can be
selected from T, D, S, L, A, E, and Q.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.9 can be
selected from D, G, and E.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.10 can be
selected from T, S, R, G, A, S, and N.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.11 can be
W.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.12 can be
selected from V and E.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.13 can be
C.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.14 can be
selected from V and I.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.13 can be
F.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.1 can be
selected from A, G, P, S, and T.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.1 can be
selected from H, K, and R.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.2 can be
selected from A, G, P, S, and T.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.2 can be
selected from H, K, and R.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.2 can be
selected from R and G.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.3 can be
C.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.4 can be
selected from A, G, P, S, and T.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.4 can be
selected from S and T.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.5 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.5 can be
L.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.6 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.6 can be
V.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.7 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.7 can be
selected from F, W, and Y.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.7 can be
W.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.8 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.8 can be
selected from A, G, P, S, and T.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.8 can be
A.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.9 can be
selected from D and E.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.9 can be
D.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.10 can be
selected from A, G, P, S, and T.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.10 can be
S.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.11 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.11 can be
selected from F, W, and Y.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.11 can be
W.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.12 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.12 can be
selected from D and E.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.12 can be
selected from V and E.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.12 can be
V.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.13 can be
C.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.14 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.14 can be
I.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.15 can be
F.
In IL-2R.alpha. ligands of Formula (13a)-(13c), X.sup.2 can be R,
X.sup.3 can be C, X.sup.5 can be S, X.sup.6 can be L, X.sup.7 can
be V, X.sup.8 can be W, X.sup.10 can be D, X.sup.11 can be S,
X.sup.12 can be W, X.sup.11 can be V, X.sup.14 can be C, X.sup.15
can be I, and X.sup.16 can be F.
In IL-2R.alpha. ligands of Formula (13a)-(13c),
X.sup.1 can be selected from A, D, E, G, P, S, and T;
X.sup.2 can be selected from G and R;
X.sup.3 can be C;
X.sup.4 can be selected from S and T;
X.sup.5 can be L;
X.sup.6 can be V;
X.sup.7 can be selected from F and W;
X.sup.8 can be selected from A, G, P, S, and T;
X.sup.9 can be selected from D and E;
X.sup.10 can be S;
X.sup.11 can be W;
X.sup.12 can be V;
X.sup.13 can be C;
X.sup.14 can be I; and
X.sup.15 can be F.
IL-2R.alpha. ligands provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
152 to SEQ ID NO: 166:
TABLE-US-00017 SEQ ID NO: 152 S R C S L V W T D T W V C V F SEQ ID
NO: 153 S R C T L V F D D S W V C V F SEQ ID NO: 154 R G C S L V W
S G S W E C I F SEQ ID NO: 155 Q A C Q L V W L D S W V C I F SEQ ID
NO: 156 V G C S L V W T D R W E C I F SEQ ID NO: 157 S G C S L Q W
A D G W V C I F SEQ ID NO: 158 A R C S L V W D E A W V C I F SEQ ID
NO: 159 R G C S L V W A G S W E C I F SEQ ID NO: 160 S R C S L V W
A E N W V C I F SEQ ID NO: 161 R R C T L V F L D S W E C I F SEQ ID
NO: 162 R G C T L A W E D S W V C I F SEQ ID NO: 163 R G C S L R F
A E A W E C I F SEQ ID NO: 164 A S C S L V W Q D S W V C I F SEQ ID
NO: 165 S R C S L V W A D S W V C I F SEQ ID NO: 166 G R C H L V W
S D R W E C I F
An IL-2R.alpha. ligand provided by the present disclosure can
comprise a truncated amino acid sequence of any one of SEQ ID NO:
149 to SEQ ID NO: 166.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
149 to SEQ ID NO: 166, or a truncated amino acid sequence of any
one of SEQ ID NO: 149 to SEQ ID NO: 166, wherein the amino acid
sequence can independently comprise from 1 to 4 glycines (G) (SEQ
ID NO: 1041) on the N-terminus, on the C-terminus, or on both the
N- and C-termini.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
149 to SEQ ID NO: 166, or a truncated amino acid sequence of any
one of SEQ ID NO: 149 to SEQ ID NO: 166, wherein the amino acid
sequence comprises one or more amino acid substitutions such as
from 1 to 5 amino acid substitutions.
IL-2R.alpha. ligands provided by the present disclosure can
comprise the amino acid sequence of Formula (14a) (SEQ ID NO: 167),
or the amino acid sequence of Formula (14b) (SEQ ID NO: 168):
--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10-
--X.sup.11--X.sup.12-- (14a)
--X.sup.1--C--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup-
.9--X.sup.10--X.sup.11--X.sup.12--C--X.sup.14-- (14b)
wherein, X.sup.1 can be selected from an amino acid comprising a
small hydrophobic side chain; X.sup.2 can be C; X.sup.3 can be
selected from an amino acid comprising a small hydrophobic side
chain; X.sup.4 can be selected from an amino acid comprising a
large hydrophobic side chain; X.sup.5 can be selected from an amino
acid; X.sup.6 can be selected from an amino acid comprising a large
hydrophobic side chain; X.sup.7 can be selected from an amino acid
comprising an acidic side chain or a polar neutral side chain;
X.sup.8 can be selected from an amino acid; X.sup.9 can be selected
from an amino acid; X.sup.10 can be selected from an amino acid
comprising a large hydrophobic side chain; X.sup.11 can be selected
from an amino acid comprising a large hydrophobic side chain;
X.sup.12 can be selected from an amino acid comprising a large
hydrophobic side chain or an acidic side chain; X.sup.13 can be C;
and X.sup.14 can be selected from an amino acid comprising a large
hydrophobic side chain.
In IL-2R.alpha. ligands of Formula (14a)-(14b),
X.sup.1 can be selected from A, G, P, S, and T;
X.sup.2 can be C;
X.sup.3 can be selected from A, G, P, S, and T;
X.sup.4 can be selected from F, I, L, M, V, W, and Y;
X.sup.5 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.6 can be selected from F, I, L, M, V, W, and Y;
X.sup.7 can be selected from D, E, N, Q, S, T, and Y;
X.sup.8 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.9 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.10 can be selected from F, I, L, M, V, W, and Y;
X.sup.11 can be selected from F, I, L, M, V, W, and Y;
X.sup.12 can be selected from D, E, F, I, L, M, V, W, and Y;
X.sup.13 can be C; and
X.sup.14 can be selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.1 can be
selected from G and S.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.2 can be
C.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.3 can be
selected from T, S, M, and V.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.4 can be
selected from L and V.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.5 can be
selected from K, R, M, S, T, and Q.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.6 can be
selected from W, R, and F.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.7 can be
selected from E, D, Q, N, G, and S.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.8 can be
selected from S, G, D, Q, K, and G.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.9 can be
selected from P, D, G, F, and V.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.10 can be
selected from N and W.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.11 can be
W.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.12 can be
selected from T, V, H, and E.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.13 can be
C.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.14 can be
selected from Y, E, I, and V.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.1 can be
G.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.2 can be
C.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.3 can be
selected from S and T.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.3 can be
T.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.4 can be
L.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.5 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.6 can be
W.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.7 can be
selected from D, E, Q, and N.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.8 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.9 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.10 can be
W.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.11 can be
W.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.12 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.12 can be
selected from D and E.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.12 can be
selected from E and V.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.13 can be
C.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.14 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.14 can be
selected from I and V.
In IL-2R.alpha. ligands of Formula (14a)-(14b), X.sup.1 can be G,
X.sup.2 can be C, X.sup.3 can be T, X.sup.4 can be L, X.sup.6 can
be W, X.sup.10 can be W, X.sup.11 can be W, and X.sup.11 can be
C.
In IL-2R.alpha. ligands of Formula (14a)-(14b),
X.sup.1 can be G;
X.sup.2 can be C;
X.sup.3 can be selected from T and S;
X.sup.4 can be L;
X.sup.5 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.6 can be W;
X.sup.7 can be selected from D, E, N, Q, S, T, and Y;
X.sup.8 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.9 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.10 can be W;
X.sup.11 can be W;
X.sup.12 can be selected from V and E;
X.sup.13 can be C; and
X.sup.14 can be selected from F, I, L, M, V, W, and Y.
IL-2R.alpha. ligands provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
169 to SEQ ID NO: 174:
TABLE-US-00018 SEQ ID NO: 169 G C T L K W E S P N W T C Y SEQ ID
NO: 170 S C T V R W D G D W W V C E SEQ ID NO: 171 G C S L M W Q D
G W W V C I SEQ ID NO: 172 G C T L S W N Q G W W H C V SEQ ID NO:
173 G C M L T R G K F W W E C I SEQ ID NO: 174 G C V L Q F S G V W
W E C V
An IL-2R.alpha. ligand provided by the present disclosure can
comprise a truncated amino acid sequence of any one of SEQ ID NO:
167 to SEQ ID NO: 174.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
167 to SEQ ID NO: 174, or a truncated amino acid sequence of any
one of SEQ ID NO: 167 to SEQ ID NO: 174, wherein the amino acid
sequence can independently comprise from 1 to 4 glycines (G) (SEQ
ID NO: 1041) on the N-terminus, on the C-terminus, or on both the
N- and C-termini.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
167 to SEQ ID NO: 174, or a truncated amino acid sequence of any
one of SEQ ID NO: 167 to SEQ ID NO: 174, wherein the amino acid
sequence comprises one or more amino acid substitutions such as
from 1 to 5 amino acid substitutions.
IL-2R.alpha. ligands provided by the present disclosure can
comprise the amino acid sequence of Formula (15a) (SEQ ID NO: 175),
the amino acid sequence of Formula (15b) (SEQ ID NO: 176), or the
amino acid sequence of Formula (15c) (SEQ ID NO: 177):
--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.sup.1-
1--X.sup.12--X.sup.13-- (15a)
--X.sup.2--C--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup-
.10--X.sup.11--X.sup.12--X.sup.13--C--X.sup.15-- (15b)
--X.sup.1--X.sup.2--C--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup-
.9--X.sup.10--X.sup.11--X.sup.12--X.sup.13--C--X.sup.15--X.sup.16--
(15c)
wherein, X.sup.1 can be selected from an amino acid; X.sup.2 can be
selected from an amino acid; X.sup.3 can be C; X.sup.4 can be
selected from an amino acid comprising a polar/neutral side chain
or a basic side chain; X.sup.5 can be selected from an amino acid
comprising a large hydrophobic side chain; X.sup.6 can be selected
from an amino acid; X.sup.7 can be selected from an amino acid
comprising a polar neutral side chain or a basic side chain;
X.sup.8 can be P; X.sup.9 can be G; X.sup.10 can be selected from
an amino acid; X.sup.11 can be selected from an amino acid;
X.sup.12 can be selected from an amino acid comprising a large
hydrophobic side chain; X.sup.13 can be selected from an amino acid
comprising an acidic side chain or a polar/neutral side chain;
X.sup.14 can be C; X.sup.15 can be selected from an amino acid
comprising a large hydrophobic side chain; and X.sup.16 can be
selected from an amino acid comprising a large hydrophobic side
chain.
In IL-2R.alpha. ligands of Formula (15a)-(15c),
X.sup.1 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.2 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.3 can be C;
X.sup.4 can be selected from H, K, N, Q, R, S, T, and Y;
X.sup.5 can be selected from F, I, L, M, V, W, and Y;
X.sup.6 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.7 can be selected from H, K, N, Q, R, S, T, and Y;
X.sup.8 can be P;
X.sup.9 can be G;
X.sup.10 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.11 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.12 can be selected from F, I, L, M, V, W, and Y;
X.sup.13 can be selected from D, E, N, Q, S, T, and Y;
X.sup.14 can be C;
X.sup.15 can be selected from F, I, L, M, V, W, and Y; and
X.sup.16 can be selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.1 can be
selected from Q, A, G, K, L, N, P, Q, S, and T.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.2 can be
selected from R, G, K, T, P, A, S, and H.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.3 can be
C.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.4 can be
selected from Q, M, S, R, T, I, K, R, H, and L.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.5 can be
selected from L, P, M, and V.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.6 can be
selected from S, L, R, Q, F, W, N, I, and G.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.7 can be
selected from K, H, R, W, L, N, F, and V.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.8 can be
selected from S, P, T, and L.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.9 can be
G.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.10 can be
selected from G, L, S, D, T, E, M, N, F, H, R, K, and P.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.11 can be
selected from E, Y, R, G, H, S, I, G, L, W, F, and V.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.12 can be
selected from L, W, Y, H, and V.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.13 can be
selected from G, E, V, T, Q, and A.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.14 can be
C.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.15 can be
selected from M, I, V, L, W, R, and F.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.16 can be
selected from F, S, and G.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.1 can be
selected from S and T.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.2 can be
selected from S, T, R, and K.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.3 can be
C.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.4 can be
selected from N, Q, S, T, and Y.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.4 can be
T.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.5 can be
selected from L, M, and V.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.5 can be
L.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.6 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.7 can be
selected from N, K, H, and R.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.7 can be
N.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.8 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.8 can be
selected from A, G, P, S, and T.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.8 can be
P.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.9 can be
G.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.10 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.11 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.11 can be
selected from A, G, P, S, and T.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.11 can be
G.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.12 can be
W.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.13 can be
selected from N, Q, S, T, and Y.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.13 can be
selected from D and E.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.13 can be
selected from E and Q.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.13 can be
E.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.14 can be
C.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.15 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.15 can be
selected from M, I, V, L, and F.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.15 can be
selected from I and V.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.16 can be
F.
In IL-2R.alpha. ligands of Formula (15a)-(15c), X.sup.3 can be C,
X.sup.5 can be L, X.sup.8 can be P, X.sup.9 can be G, X.sup.12 can
be W, X.sup.13 can be E, X.sup.14 can be C, and X.sup.16 can be
F.
In IL-2R.alpha. ligands of Formula (15a)-(15c),
X.sup.1 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.2 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.3 can be C;
X.sup.4 can be selected from N, Q, S, T, and Y;
X.sup.5 can be L;
X.sup.6 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.7 can be selected from N, Q, S, T, and Y;
X.sup.8 can be P;
X.sup.9 can be G;
X.sup.10 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.11 can be selected from A, G, P, S, and T;
X.sup.12 can be W;
X.sup.13 can be selected from E and Q;
X.sup.14 can be C;
X.sup.15 can be selected from F, I, L, M, V, W, and Y; and
X.sup.16 can be F.
IL-2R.alpha. ligands provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
178 to SEQ ID NO: 195:
TABLE-US-00019 SEQ ID NO: 178 Q R C Q L S W S G G E L G C M F SEQ
ID NO: 179 A G C M L L K P G L Y W E C I F SEQ ID NO: 180 A R C S L
H H T G S R Y E C I F SEQ ID NO: 181 A T C M L R L L G D G W G C V
F SEQ ID NO: 182 G P C R L S N P G T G W E C I F SEQ ID NO: 183 K G
C T L Q N P G S G W V C L F SEQ ID NO: 184 L A C I L S K P G E H W
E C L F SEQ ID NO: 185 N G C T S F S S G M S W T C V Y SEQ ID NO:
186 N S C I L S N P G L G W Q C V F SEQ ID NO: 187 N T C K L F R S
G N I W Q C I F SEQ ID NO: 188 P S C R L W N P G F G W E C I F SEQ
ID NO: 189 Q S C T L Q R L G H L Y Q C W F SEQ ID NO: 190 S A C T P
N W T G R W W E C V F SEQ ID NO: 191 S K C H L I V S G K F H E C V
F SEQ ID NO: 192 S S C T L F N P G T G W T C V F SEQ ID NO: 193 S T
C R M G N P G G V W G C Y F SEQ ID NO: 194 T H C L V Q W P G P V V
A C R S SEQ ID NO: 195 T R C R L L K L G S L W E C F G
An IL-2R.alpha. ligand provided by the present disclosure can
comprise a truncated amino acid sequence of any one of SEQ ID NO:
175 to SEQ ID NO: 195.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
175 to SEQ ID NO: 195, or a truncated amino acid sequence of any
one of SEQ ID NO: 175 to SEQ ID NO: 195, wherein the amino acid
sequence can independently comprise from 1 to 4 glycines (G) (SEQ
ID NO: 1041) on the N-terminus, on the C-terminus, or on both the
N- and C-termini.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
175 to SEQ ID NO: 195, or a truncated amino acid sequence of any
one of SEQ ID NO: 175 to SEQ ID NO: 195, wherein the amino acid
sequence comprises one or more amino acid substitutions such as
from 1 to 5 amino acid substitutions.
IL-2R.alpha. ligands provided by the present disclosure can
comprise the amino acid sequence of Formula (16a) (SEQ ID NO: 196),
or the amino acid sequence of Formula (16b) (SEQ ID NO: 197):
--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10-
--X.sup.11--X.sup.12--X.sup.13-- (16a)
--X.sup.1--C--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup-
.9--X.sup.10--X.sup.11--X.sup.12--X.sup.13--C--X.sup.15-- (16b)
wherein, X.sup.1 can be selected from an amino acid; X.sup.2 can be
C; X.sup.3 can be selected from an amino acid comprising a basic
side chain; X.sup.4 can be selected from an amino acid comprising a
large hydrophobic side chain; X.sup.5 can be selected from an amino
acid comprising a basic side chain or a polar/neutral side chain;
X.sup.6 can be selected from an amino acid comprising a basic side
chain or a polar/neutral side chain; X.sup.7 can be selected from
an amino acid; X.sup.8 can be selected from an amino acid; X.sup.9
can be selected from an amino acid; X.sup.10 can be selected from
an amino acid; X.sup.11 can be selected from an amino acid;
X.sup.12 can be selected from an amino acid comprising an aromatic
side chain or a large hydrophobic side chain; X.sup.13 can be
selected from an amino acid comprising an acidic side chain;
X.sup.14 can be C; and X.sup.1 can be selected from an amino acid
comprising a large hydrophobic side chain.
In IL-2R.alpha. ligands of Formula (16a)-(16b),
X.sup.1 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.2 can be selected from C;
X.sup.3 can be selected from H, K, and R;
X.sup.4 can be selected from F, I, L, M, V, W, and Y;
X.sup.5 can be selected from H, K, N, Q, R, S, T, and Y;
X.sup.6 can be selected from H, K, N, Q, R, S, T, and Y;
X.sup.7 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.8 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.9 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.10 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.11 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.12 can be selected from F, H, I, L, M, V, W, and Y;
X.sup.13 can be selected from D and E;
X.sup.14 can be C; and
X.sup.15 can be selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.1 can be
selected from A, K, N, R, and T.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.2 can be
C.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.3 can be
selected from W, R, and T.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.4 can be
selected from R, L, and V.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.5 can be
selected from S, R, Q, K, and H.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.6 can be
selected from W, Q, H, K, F, and R.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.7 can be
selected from R, M, L, A, D, S, and I.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.8 can be
selected from Y, S, P, G, and A.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.9 can be
selected from P, R, Y, G, Q, P, and L.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.10 can be
selected from T, G, P, N, T, N, and A.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.11 can be
selected from R, G, F, T, G, S, and E.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.12 can be
selected from T and W.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.13 can be
selected from F, E, and S.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.14 can be
C.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.15 can be
selected from S, L, N, I, and V.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.2 can be
C.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.3 can be
R.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.4 can be
selected from L and V.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.5 can be
selected from R, K, and H.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.6 can be
selected from R, K, and H.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.7 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.8 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.8 can be
G.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.9 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.10 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.11 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.12 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.12 can be
selected from F, W, and Y.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.12 can be
W.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.13 can be
E.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.14 can be
C.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.15 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.15 can be
selected from L, I, and V.
In IL-2R.alpha. ligands of Formula (16a)-(16b), X.sup.2 can be C,
X.sup.3 can be R, X.sup.12 can be W, X.sup.11 can be E, and
X.sup.14 can be C.
In IL-2R.alpha. ligands of Formula (16a)-(16b),
X.sup.2 can be C;
X.sup.3 can be R;
X.sup.4 can be selected from F, I, L, M, V, W, and Y;
X.sup.5 can be selected from N, Q, S, T, and Y;
X.sup.6 can be selected from N, Q, S, T, and Y;
X.sup.7 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.8 can be selected from A, G, P, S, and T;
X.sup.9 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.10 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.11 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.12 can be W;
X.sup.13 can be E;
X.sup.14 can be C; and
X.sup.15 can be selected from F, I, L, M, V, W, and Y.
IL-2R.alpha. ligands provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
189 to SEQ ID NO: 204:
TABLE-US-00020 SEQ ID NO: 198 A C W R S W R Y P T R T F C S SEQ ID
NO: 199 K C R L R Q M S R G G W E C L SEQ ID NO: 200 N C R V R H L
P Y P F W S C L SEQ ID NO: 201 R C R L Q K A G G N T W E C I SEQ ID
NO: 202 R C T L R F D A Q T G W E C N SEQ ID NO: 203 T C R L K R S
G P N S W E C I SEQ ID NO: 204 T C T V H R I G L A E W E C V
An IL-2R.alpha. ligand provided by the present disclosure can
comprise a truncated amino acid sequence of any one of SEQ ID NO:
196 to SEQ ID NO: 204.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
196 to SEQ ID NO: 204, or a truncated amino acid sequence of any
one of SEQ ID NO: 196 to SEQ ID NO: 204, wherein the amino acid
sequence can independently comprise from 1 to 4 glycines (G) (SEQ
ID NO: 1041) on the N-terminus, on the C-terminus, or on both the
N- and C-termini.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
196 to SEQ ID NO: 204, or a truncated amino acid sequence of any
one of SEQ ID NO: 196 to SEQ ID NO: 204, wherein the amino acid
sequence comprises one or more amino acid substitutions such as
from 1 to 5 amino acid substitutions.
IL-2R.alpha. ligands provided by the present disclosure can
comprise the amino acid sequence of Formula (17a) (SEQ ID NO: 205),
the amino acid sequence of Formula (17b) (SEQ ID NO: 206), or the
amino acid sequence of Formula (17c) (SEQ ID NO: 207):
--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.sup.1-
1--X.sup.12--X.sup.13-- (17a)
--X.sup.2--C--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup-
.10--X.sup.11--X.sup.12--X.sup.13--C--X.sup.15-- (17b)
--X.sup.1--X.sup.2--C--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup-
.9--X.sup.10--X.sup.11--X.sup.12--X.sup.13--CX.sup.15--X.sup.16--
(17c)
wherein, X.sup.1 can be selected from an amino acid comprising a
large hydrophobic side chain; X.sup.2 can be selected from an amino
acid comprising a basic side chain; X.sup.3 can be C; X.sup.4 can
be selected from an amino acid comprising a basic side chain;
X.sup.5 can be selected from an amino acid comprising a basic side
chain or an aromatic side chain or a large hydrophobic side chain;
X.sup.6 can be selected from an amino acid; X.sup.7 can be selected
from an amino acid; X.sup.8 can be P; X.sup.9 can be G; X.sup.10
can be selected from an amino acid; X.sup.11 can be selected from
an amino acid; X.sup.12 can be selected from an amino acid;
X.sup.13 can be selected from an amino acid; X.sup.14 can be C;
X.sup.15 can be selected from an amino acid comprising a large
hydrophobic side chain; and X.sup.16 can be selected from an amino
acid comprising a small hydrophobic side chain.
In IL-2R.alpha. ligands of Formula (17a)-(17c),
X.sup.1 can be selected from F, I, L, M, V, W, and Y;
X.sup.2 can be selected from H, K, and R;
X.sup.3 can be C;
X.sup.4 can be selected from H, K, and R;
X.sup.5 can be selected from F, H, I, K, L, M, R, V, W, and Y;
X.sup.6 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.7 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.8 can be P;
X.sup.9 can be G;
X.sup.10 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.11 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.12 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.13 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.14 can be C;
X.sup.15 can be selected from F, I, L, M, V, W, and Y; and
X.sup.16 can be selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.1 can be
V.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.2 can be
selected from K, R, T, and Y.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.3 can be
C.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.4 can be
selected from K, F, R, and Y.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.5 can be
selected from L, M, V, and R.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.6 can be
selected from V, S, A, L, and E.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.7 can be
selected from M, E, R, Y, V, and K.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.8 can be
P.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.9 can be
G.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.10 can be
selected from S, R, L, Q, V, and G.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.11 can be
selected from G, V, T, M, and E.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.12 can be
selected from W, S, W, A, and M.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.13 can be
selected from A, Y, E, V, and H.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.14 can be
C.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.14 can be
selected from H, T, L, V, F, and R.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.14 can be
selected from F, A, and S.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.1 can be
V.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.2 can be
R.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.3 can be
C.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.4 can be
R.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.5 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.5 can be
selected from F, W, and Y.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.5 can be
selected from H, K, and R.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.6 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.7 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.8 can be
P.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.9 can be
G.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.10 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.11 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.12 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.13 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.14 can be
C.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.15 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.16 can be
S.
In IL-2R.alpha. ligands of Formula (17a)-(17c), X.sup.1 can be V,
X.sup.2, can be R, X.sup.3 can be C, X.sup.4 can be R, X.sup.14 can
be C, and X.sup.16 can be S.
In IL-2R.alpha. ligands of Formula (17a)-(17c),
X.sup.1 can be V;
X.sup.2 can be R;
X.sup.3 can be C;
X.sup.4 can be R;
X.sup.5 can be selected from H, F, I, K, L, M, R, V, W, and Y;
X.sup.6 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.7 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.8 can be P;
X.sup.9 can be G;
X.sup.10 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.11 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.12 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.13 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.14 can be C;
X.sup.15 can be selected from F, I, L, M, V, W, and Y; and
X.sup.16 can be S.
IL-2R.alpha. ligands provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
208 to SEQ ID NO: 213:
TABLE-US-00021 SEQ ID NO: 208 V K C K L V N P G S G W A C H F SEQ
ID NO: 209 V R C F M S E P G R V S Y C T A SEQ ID NO: 210 V R C R L
A R P G L T W E C L S SEQ ID NO: 211 V R C R V L Y P G Q M A V C V
S SEQ ID NO: 212 V T C Y R A V P G V E A Y C F S SEQ ID NO: 213 V Y
C R R E K P G G E M H C R S
An IL-2R.alpha. ligand provided by the present disclosure can
comprise a truncated amino acid sequence of any one of SEQ ID NO:
205 to SEQ ID NO: 213.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
205 to SEQ ID NO: 213, or a truncated amino acid sequence of any
one of SEQ ID NO: 205 to SEQ ID NO: 213, wherein the amino acid
sequence can independently comprise from 1 to 4 glycines (G) (SEQ
ID NO: 1041) on the N-terminus, on the C-terminus, or on both the
N- and C-termini.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
205 to SEQ ID NO: 213, or a truncated amino acid sequence of any
one of SEQ ID NO: 205 to SEQ ID NO: 213, wherein the amino acid
sequence comprises one or more amino acid substitutions such as
from 1 to 5 amino acid substitutions.
IL-2R.alpha. ligands provided by the present disclosure can
comprise the amino acid sequence of Formula (18a) (SEQ ID NO: 214),
the amino acid sequence of Formula (18b) (SEQ ID NO: 215), or the
amino acid sequence of Formula (18c) (SEQ ID NO: 216):
--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.sup.1-
1--X.sup.12--X.sup.13-- (18a)
--X.sup.2--C--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup-
.10--X.sup.11--X.sup.12--X.sup.13--C--X.sup.15-- (18b)
--X.sup.1--X.sup.2--C--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup-
.9--X.sup.10--X.sup.11--X.sup.12--X.sup.13--C--X.sup.15--X.sup.16--
(18c)
wherein, X.sup.1 can be selected from an amino acid; X.sup.2 can be
selected from an amino acid; X.sup.3 can be C; X.sup.4 can be
selected from an amino acid comprising an aromatic side chain or a
large hydrophobic side chain; X.sup.5 can be selected from an amino
acid comprising a large hydrophobic side chain; X.sup.6 can be
selected from an amino acid; X.sup.7 can be selected from an amino
acid; X.sup.8 can be P; X.sup.9 can be G; X.sup.10 can be selected
from an amino acid; X.sup.11 can be selected from an amino acid;
X.sup.12 can be selected from an amino acid; X.sup.13 can be
selected from an amino acid comprising an aromatic side chain or a
large hydrophobic side chain; X.sup.14 can be C; X.sup.15 can be
selected from an amino acid; and X.sup.16 can be selected from an
amino acid comprising a large hydrophobic side chain.
In IL-2R.alpha. ligands of Formula (18a)-(18c),
X.sup.1 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.2 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.3 can be C;
X.sup.4 can be selected from F, H, I, L, M, V, W, and Y;
X.sup.5 can be selected from F, I, L, M, V, W, and Y;
X.sup.6 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.7 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.8 can be P;
X.sup.9 can be G;
X.sup.10 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.11 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.12 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.13 can be selected from F, H, I, L, M, V, W, and Y;
X.sup.14 can be C;
X.sup.15 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y; and
X.sup.16 can be selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.1 can be
selected from A, H, Q, R, T, and V.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.2 can be
selected from T, G, L, D, and K.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.3 can be
C.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.4 can be
selected from H, T, P, A, F, Q, and Y.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.5 can be
selected from L, W, G, I, E, M, and R.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.6 can be
selected from L, T, S, M, and N.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.7 can be
selected from A, K, D, E, W, T, and S.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.8 can be
P.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.9 can be
G.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.10 can be
selected from V, A, S, T, D, Q, and V.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.11 can be
selected from D, E, W, S, R, and I.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.12 can be
selected from N, W, G, V, P, and A.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.13 can be
selected from T, V, P, F, Y, and W.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.14 can be
C.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.14 can be
selected from I, S, P, D, H, T, and V.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.14 can be
selected from F, L, N, I, T, and G.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.1 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.2 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.3 can be
C.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.4 can be
selected from F, H, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.4 can be
selected from F, W, and Y.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.5 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.6 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.7 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.8 can be
P.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.9 can be
G.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.10 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.11 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.12 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.13 can be
selected from F, H, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.13 can be
selected from F, W, and Y.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.14 can be
C.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.15 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.16 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (18a)-(18c), X.sup.3 can be C,
X.sup.8 can be P, X.sup.9 can be G, and X.sup.14 can be C.
In IL-2R.alpha. ligands of Formula (18a)-(18c),
X.sup.1 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.2 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.3 can be C;
X.sup.4 can be selected from F, H, W, and Y;
X.sup.5 can be selected from F, I, L, M, V, W, and Y;
X.sup.6 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.7 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.8 can be P;
X.sup.9 can be G;
X.sup.10 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.11 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.12 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.13 can be selected from F, H, W, and Y;
X.sup.14 can be C;
X.sup.15 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y; and
X.sup.16 can be selected from F, I, L, M, V, W, and Y.
IL-2R.alpha. ligands provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
217 to SEQ ID NO: 224:
TABLE-US-00022 SEQ ID NO: 217 A T C H L L A P G V D N T C I F SEQ
ID NO: 218 H G C T L T K P G A E W V C S F SEQ ID NO: 219 Q L C P W
S D P G S W G P C P L SEQ ID NO: 220 R D C A G M E P G T S V F C D
N SEQ ID NO: 221 R D C F I L E P G T S V Y C D L SEQ ID NO: 222 T D
C Q E T W P G D R P W C H I SEQ ID NO: 223 V K C F M S T P G Q I A
Y C T T SEQ ID NO: 224 V K C Y R N S P G V E A Y C V G
An IL-2R.alpha. ligand provided by the present disclosure can
comprise a truncated amino acid sequence of any one of SEQ ID NO:
214 to SEQ ID NO: 224.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
214 to SEQ ID NO: 224, or a truncated amino acid sequence of any
one of SEQ ID NO: 214 to SEQ ID NO: 224, wherein the amino acid
sequence can independently comprise from 1 to 4 glycines (G) (SEQ
ID NO: 1041) on the N-terminus, on the C-terminus, or on both the
N- and C-termini.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
214 to SEQ ID NO: 224, or a truncated amino acid sequence of any
one of SEQ ID NO: 214 to SEQ ID NO: 224, wherein the amino acid
sequence comprises one or more amino acid substitutions such as
from 1 to 5 amino acid substitutions.
IL-2R.alpha. ligands provided by the present disclosure can
comprise the amino acid sequence of Formula (19a) (SEQ ID NO: 225),
or the amino acid sequence of Formula (19b) (SEQ ID NO: 226):
--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10-
--X.sup.11--X.sup.12-- (19a)
--X.sup.1--C--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup-
.9--X.sup.10--X.sup.11--X.sup.12--C--X.sup.14-- (19b)
wherein, X.sup.1 can be selected from an amino acid; X.sup.2 can be
C; X.sup.3 can be selected from an amino acid comprising an acidic
side chain or a polar/neutral side chain; X.sup.4 can be selected
from an amino acid comprising an acidic side chain or a
polar/neutral side chain; X.sup.5 can be selected from an amino
acid comprising a large hydrophobic side chain; X.sup.6 can be
selected from an amino acid comprising a polar/neutral side chain;
X.sup.7 can be selected from an amino acid; X.sup.8 can be selected
from an amino acid; X.sup.9 can be selected from an amino acid
comprising a large hydrophobic side chain; X.sup.10 can be selected
from an amino acid; X.sup.11 can be selected from an amino acid;
X.sup.12 can be selected from an amino acid; X.sup.13 can be C; and
X.sup.14 can be selected from an amino acid.
In IL-2R.alpha. ligands of Formula (19a)-(19b),
X.sup.1 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.2 can be C;
X.sup.3 can be selected from D, E, N, Q, S, T, and Y;
X.sup.4 can be selected from D, E, N, Q, S, T, and Y;
X.sup.5 can be selected from F, I, L, M, V, W, and Y;
X.sup.6 can be selected from N, Q, S, T, and Y;
X.sup.7 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.8 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.9 can be selected from F, I, L, M, V, W, and Y;
X.sup.10 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.11 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.12 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y;
X.sup.13 can be C; and
X.sup.14 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.1 can be
selected from D, P, S, T, W, and Y.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.2 can be
C.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.3 can be
selected from L, Q, M, E, W, and H.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.4 can be
selected from D, R, S, E, and L.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.5 can be
selected from L, P, F, and V.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.6 can be
selected from R, A, K, H, and W.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.7 can be
selected from G, E, K, R, D, G, and Q.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.8 can be
selected from T, Y, S, M, Q, and D.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.9 can be
selected from V, Y, and D.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.10 can be
selected from G, S, E, N, and Y.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.11 can be
selected from M, Q, W, V, E, N, R, L, and M.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.12 can be
selected from V, Q, W, V, E, N, R, L, and M.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.13 can be
C.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.14 can be
selected from Q, L, D, N, I, P, and F.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.1 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.2 can be
C.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.3 can be
selected from H, N, Q, S, T, and Y.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.3 can be
selected from D and E.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.3 can be
selected from Q and E.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.4 can be
selected from D and E.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.5 can be
L.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.6 can be
selected from R, H, and K.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.7 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.8 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.9 can be
Y.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.10 can be
selected from A, G, P, S, and T.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.11 can be
selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,
and Y.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.12 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.12 can be
selected from V, L, and M.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.13 can be
C.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.14 can be
selected from F, I, L, M, V, W, and Y.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.14 can be
selected from F, I, and L.
In IL-2R.alpha. ligands of Formula (19a)-(19b), X.sup.2 can be C,
X.sup.5 can be L, and X.sup.13 can be C.
In IL-2R.alpha. ligands of Formula (19a)-(19b),
X.sup.1 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.2 can be C;
X.sup.3 can be selected from D, E, N, Q, S, T, and Y;
X.sup.4 can be selected from D, E, N, Q, S, T, and Y;
X.sup.5 can be L;
X.sup.6 can be selected from A, G, H, K, P, S, and T;
X.sup.7 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.8 can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,
R, S, T, V, W, and Y;
X.sup.9 can be selected from F, I, L, M, V, W, and Y;
X.sup.10 can be selected from A, G, P, S, and T;
X.sup.11 can be selected from A, D, E, F, G, H, I, K, L, M, N, P,
Q, R, S, T, V, W, and Y; and
X.sup.12 can be selected from F, I, L, M, V, W, and Y;
X.sup.13 can be C; and
X.sup.14 can be selected from F, I, L, M, V, W, and Y.
IL-2R.alpha. ligands provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
227 to SEQ ID NO: 234:
TABLE-US-00023 SEQ ID NO: 227 D C L D L R G T V G M V C Q SEQ ID
NO: 228 P C Q R L A E Y Y S Q Q C L SEQ ID NO: 229 S C M D L K G S
V G W V C D SEQ ID NO: 230 T C E S L A K M Y E V E C N SEQ ID NO:
231 T C E S L A R M Y N E N C I SEQ ID NO: 232 W C W E P H D Q Y Y
V R C P SEQ ID NO: 233 Y C H D F K G T V G T L C I SEQ ID NO: 234 G
C Q L V W Q D D S Y M C F Y
An IL-2R.alpha. ligand provided by the present disclosure can
comprise a truncated amino acid sequence of any one of SEQ ID NO:
225 to SEQ ID NO: 234.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
225 to SEQ ID NO: 234, or a truncated amino acid sequence of any
one of SEQ ID NO: 225 to SEQ ID NO: 234, wherein the amino acid
sequence can independently comprise from 1 to 4 glycines (G) (SEQ
ID NO: 1041) on the N-terminus, on the C-terminus, or on both the
N- and C-termini.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
225 to SEQ ID NO: 234, or a truncated amino acid sequence of any
one of SEQ ID NO: 225 to SEQ ID NO: 234, wherein the amino acid
sequence comprises one or more amino acid substitution such as from
1 to 5 amino acid substitutions.
IL-2R.alpha. ligands provided by the present disclosure can
comprise the amino acid sequence of Formula (20a) (SEQ ID NO: 235),
or the amino acid sequence of Formula (20b) (SEQ ID NO: 236):
--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10-
--X.sup.11--X.sup.12-- (20a)
--X.sup.1--C--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup-
.9--X.sup.10--X.sup.11--X.sup.12--C--X.sup.14-- (20b)
wherein, X.sup.1 can be W; X.sup.2 can be C; X.sup.3 can be
selected from F, I, L, M, V, W, and Y; X.sup.4 can be G; X.sup.5
can be Q; X.sup.6 can be P; X.sup.7 can be L; X.sup.8 can be
selected from F, I, L, M, V, W, and Y; X.sup.9 can be R; X.sup.10
can be selected from H, N, Q, F, I, L, M, V, W, and Y; X.sup.11 can
be G; X.sup.12 can be S; X.sup.13 can be C; and X.sup.14 can be
K.
In IL-2R.alpha. ligands of Formula (20a)-(20b), X.sup.3 can be
selected from I and V.
In IL-2R.alpha. ligands of Formula (20a)-(20b), X.sup.8 can be
selected from F and Y.
In IL-2R.alpha. ligands of Formula (20a)-(20b), X.sup.10 can be
selected from F, I, L, M, N, Q, S, T, V, W, and Y.
In IL-2R.alpha. ligands of Formula (20a)-(20b), X.sup.10 can be
selected from L and Q.
In IL-2R.alpha. ligands of Formula (20a)-(20b), X.sup.1 can be W,
X.sup.2 can be C, X.sup.4 can be G, X.sup.5 can be Q, X.sup.6 can
be P, X.sup.7 can be L, X.sup.9 can be R, X.sup.11 can be G,
X.sup.12 can be S, X.sup.11 can be C, and X.sup.14 can be K.
In IL-2R.alpha. ligands of Formula (20a)-(20b),
X.sup.1 can be W;
X.sup.2 can be C;
X.sup.3 can be selected from I and V;
X.sup.4 can be G;
X.sup.5 can be Q;
X.sup.6 can be P;
X.sup.7 can be L;
X.sup.8 can be selected from F and Y;
X.sup.9 can be R;
X.sup.10 can be selected from F, H, I, L, M, N, Q, S, T, V, W, and
Y;
X.sup.11 can be G;
X.sup.12 can be S;
X.sup.13 can be C; and
X.sup.14 can be K.
IL-2R.alpha. ligands provided by the present disclosure can
comprise an amino acid sequence selected from an one of SE ID NO:
237 to SE ID NO: 307:
TABLE-US-00024 SEQ ID NO: 237 W C I G Q P L F R Q G S C K SEQ ID
NO: 238 W C V G Q P L Y R L G S C K SEQ ID NO: 239 W D Q F Q L G W
E A G V A A SEQ ID NO: 240 F L P W P V Y F S Q V L G G G SEQ ID NO:
241 Y V M C S A F G C K S I SEQ ID NO: 242 H V I C S V N G G C R G
SEQ ID NO: 243 I R F C L R S E P T A C W I V SEQ ID NO: 244 I R C R
Y E K Q S G I C L F SEQ ID NO: 245 G G C S L V W A D S W V C I F
SEQ ID NO: 246 G C S L M W Q D G W W V C I SEQ ID NO: 247 E W E C R
F L P G R R G C S L F SEQ ID NO: 248 K G C T L Q N P G S G W V C L
F SEQ ID NO: 249 T C R L K R S G P N S W E C I SEQ ID NO: 250 W C I
G Q P L F R Q G S C K SEQ ID NO: 251 A V S C N S W R C I P W SEQ ID
NO: 252 A V C C D G N S C R R C SEQ ID NO: 253 F V H C S L M G C W
C G SEQ ID NO: 254 R C L D L G G S V G L V C F SEQ ID NO: 255 V C F
N F R G T V G R H C W SEQ ID NO: 256 V R C R Q N E P G G A Y W C S
S SEQ ID NO: 257 C V L R E G A E G W E C V W R SEQ ID NO: 258 C R M
M Q G T Y G W T C L F SEQ ID NO: 259 C I L N D T I Q G W V C I Y
SEQ ID NO: 260 C T L Y R S A P G V W L C I F SEQ ID NO: 261 C L V F
D Q Y G N Y K R R C SEQ ID NO: 262 I V C C N M F G C H T C R N SEQ
ID NO: 263 Q V C C T S R G C R V C A P V SEQ ID NO: 264 R V C C S M
V G C R S C N L SEQ ID NO: 265 R V C C T F A G C R V C H K SEQ ID
NO: 266 R V C C T S D G C R G C R Q SEQ ID NO: 267 T V C C T V Q G
C W P C S R SEQ ID NO: 268 V C C H Q T F G C Y R C K Q SEQ ID NO:
269 C V V C S A L G C R A C V P R SEQ ID NO: 270 V W D C F V R G W
E A G V A A V G E SEQ ID NO: 271 L T C L I F K P G T H R H C P V
SEQ ID NO: 272 R Y C S P L I P G S A L G C P R SEQ ID NO: 273 I R C
R L D P P G S Y K T C V F SEQ ID NO: 274 R G V I C N H A G C R I W
Y G SEQ ID NO: 275 T T Q S C T L R Y C W L L Q SEQ ID NO: 276 W W I
S C L R D L R C L E Y F SEQ ID NO: 277 R H A C K T W Y R M C I V S
SEQ ID NO: 278 A V S C S R L T G R C H S L SEQ ID NO: 279 W V A C N
R V T G S C R P I SEQ ID NO: 280 S H G V C C T Q S S C R S C R SEQ
ID NO: 281 W V A C N R L S G C C R P I SEQ ID NO: 282 H T V C C Q D
W G C R S C S G SEQ ID NO: 283 M A C C T P R G C R P C SEQ ID NO:
284 R S V C C S S Y G C R A C F G SEQ ID NO: 285 C K L T C T S S T
C S C V F SEQ ID NO: 286 C M L K C T N A I C E C I F SEQ ID NO: 287
C R V W C N Q A E C M C I F SEQ ID NO: 288 S R C S F D V T K Q E C
V F SEQ ID NO: 289 L E C Q P Y R G P L Y Y C Q D SEQ ID NO: 290 S I
C C T P Q L C H S C D G SEQ ID NO: 291 T T C C T S E G C H K C I T
L SEQ ID NO: 292 C V A C S S D G C S P I I C SEQ ID NO: 293 A I C S
E D E G G E L C C W H SEQ ID NO: 294 H E I C C G P P G C H S C S V
T SEQ ID NO: 295 L S V C S C P P G Q L Y C M V E SEQ ID NO: 296 S T
W C C L H P G V G E C Q A V SEQ ID NO: 297 V T Q C F D G P G S F R
C C Y Q SEQ ID NO: 298 R Q C N C L S P G E L V N C Q Q SEQ ID NO:
299 M V S C T D L G C V V V G G G SEQ ID NO: 300 V V H C L Q S G C
Y S V G S G SEQ ID NO: 301 T I K C G S S G W C W V E A G SEQ ID NO:
302 M V S C T D L G C V V V G G G SEQ ID NO: 303 H E I C C G P P G
C H S C S V T SEQ ID NO: 304 L S V C S C P P G Q L Y C M V E SEQ ID
NO: 305 S T W C C L H P G V G E C Q A V SEQ ID NO: 306 V T Q C F D
G P G S F R C C Y Q SEQ ID NO: 307 R Q C N C L S P G E L V N C Q
Q
An IL-2R.alpha. ligand provided by the present disclosure can
comprise a truncated amino acid sequence of any one of SEQ ID NO:
235 to SEQ ID NO: 307.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
235 to SEQ ID NO: 307, or a truncated amino acid sequence of any
one of SEQ ID NO: 235 to SEQ ID NO: 307, wherein the amino acid
sequence can independently comprise from 1 to 4 glycines (G) (SEQ
ID NO: 1041) on the N-terminus, on the C-terminus, or on both the
N- and C-termini.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
235 to SEQ ID NO: 307, or a truncated amino acid sequence of any
one of SEQ ID NO: 235 to SEQ ID NO: 307, wherein the amino acid
sequence comprises one or more amino acid substitution such as from
1 to 5 amino acid substitutions.
IL-2R.alpha. ligands provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
400 to SEQ ID NO: 423:
TABLE-US-00025 SEQ ID NO: 400 W D D F I L G W E A G V A A V G E V
SEQ ID NO: 401 F L P W P V Y F S Q V L G G R R SEQ ID NO: 402 Y V M
C S A F G C K S I G G SEQ ID NO: 403 H V I C S V N G G C R G G G
SEQ ID NO: 404 G G I R F C L R S E P T A C W I V G G SEQ ID NO: 405
G G I R C R Y E K Q S G I C L F G G SEQ ID NO: 423 G G G G C S L V
W A D S W V C I F G G SEQ ID NO: 406 G G G C S L M W Q D G W W V C
I G G SEQ ID NO: 407 G G E W E C R F L P G R R G C S L F G G SEQ ID
NO: 408 G G K G C T L Q N P G S G W V C L F G G SEQ ID NO: 409 G G
T C R L K R S G P N S W E C I G G SEQ ID NO: 410 G G W C I G Q P L
F R Q G S C K G G SEQ ID NO: 411 F V L C G L Q G C R S G G SEQ ID
NO: 412 F V P W D E Y F L Q I L G G SEQ ID NO: 413 G G G W V I C S
A L G C P F G G SEQ ID NO: 414 G G G R R F C L R S E P T A C W T V
G G SEQ ID NO: 415 G G G S R C S L V W A D S W V C I F G G SEQ ID
NO: 416 G G D W E C L F L P G R R G C T L F G G SEQ ID NO: 417 F I
P W D E Y F A Q L L G G SEQ ID NO: 418 F V P W D V Y F S Q I L G G
SEQ ID NO: 419 F I P W D E Y F K Q V L G G SEQ ID NO: 420 F V P W P
E Y F L Q I M G G SEQ ID NO: 421 F I P W E E Y F S Q L L G G SEQ ID
NO: 422 F I P W P E Y F S Q L L G G
An IL-2R.alpha. ligand provided by the present disclosure can
comprise a truncated amino acid sequence of any one of SEQ ID NO:
400 to SEQ ID NO: 423.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
400 to SEQ ID NO: 423, or a truncated amino acid sequence of any
one of SEQ ID NO: 400 to SEQ ID NO: 423, wherein the amino acid
sequence can independently comprise from 1 to 4 glycines (G) (SEQ
ID NO: 1041) on the N-terminus, on the C-terminus, or on both the
N- and C-termini.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
400 to SEQ ID NO: 423, or a truncated amino acid sequence of any
one of SEQ ID NO: 400 to SEQ ID NO: 423, wherein the amino acid
sequence comprises one or more amino acid substitutions such as
from 1 to 5 amino acid substitutions.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence selected from any one of SEQ ID NO:
1 to SEQ ID NO: 307 and SEQ ID NO. 400 to SEQ ID NO: 423.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence having greater than 70%, greater
than 75%, greater than 80%, greater than 85%, greater than 90%, or
greater than 95% sequence similarity to any one of SEQ ID NO: 1 to
SEQ ID NO: 307 and SEQ ID NO. 400 to SEQ ID NO: 423.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise a truncated amino acid sequence of any one of SEQ ID NO: 1
to SEQ ID NO: 307 and SEQ ID NO. 400 to SEQ ID NO: 423.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise an amino acid sequence having greater than 70%, greater
than 75%, greater than 80%, greater than 85%, greater than 90%, or
greater than 95% sequence similarity to a truncated amino acid
sequence of any one of SEQ ID NO: 1 to SEQ ID NO: 307 and SEQ ID
NO. 400 to SEQ ID NO: 423.
IL-2R.alpha. ligands provided by the present disclosure can
comprise an amino acid sequence selected from SEQ ID NO: 1 to SEQ
ID NO: 307 independently comprising one or more such as from 1 to 5
or from 1 to 3 of the following conservative substitutions: amino
acids having a small hydrophobic side chain comprising alanine (A),
glycine (G), proline (P), serine (S) and threonine (T); amino acids
having a hydroxyl-containing side chain comprising serine (S) or
threonine (T); amino acids having an acidic side chain comprising
aspartate (D) and glutamate (E); amino acids having a polar neutral
side chain comprising histidine (H), asparagine (N), glutamine (Q),
serine (S), threonine (T), and tyrosine (Y); amino acids having a
basic side chain comprising arginine (R), lysine (K), or histidine
(H); and amino acids having a large hydrophobic side chain
comprising isoleucine (I), leucine (L), methionine (M), valine (V),
phenylalanine (F), tyrosine (Y), or tryptophan (W).
Small peptidyl IL-2R.alpha. ligands provided by the present
disclosure can include naturally amino acids or can be modified to
include non-natural amino acids. Because the small peptidyl
IL-2R.alpha. ligands can be chemically synthesized, the peptidyl
IL-2R.alpha. ligands can be modified using natural and/or
non-natural amino acids to optimize potency and efficacy, and to
improve metabolic stability. The small peptidyl IL-2R.alpha.
ligands also allow such modifications to be made with a low
likelihood of inducing immunogenicity. Also, due to their chemical
malleability, peptides can be caged to construct a reversibly
inactive prodrug using cell-specific environmental triggers such as
proteases, or complexes sensitive to low pH. For example, the
pH-dependent binding properties of peptides can be optimized by use
of non-natural amino acids having sidechain ionizable groups with a
pKa in the range of pH 5.0 to pH 8.0. As with proteins,
pharmacokinetic-enhancing moieties, such as polyethylene glycol
(PEG), can be appended to peptides, either as part of, or
independent of, a "caging" strategy. Also, sites on a peptide can
be reserved for attaching a variety of cell targeting moieties,
such as tumor-specific antibodies and immune cell-specific
targeting moieties. These features of peptidyl IL-2R.alpha. ligands
can be exploited in the design of optimal therapeutic candidates
based on the peptidyl IL-2R.alpha. ligands provided by the present
disclosure.
In addition to peptides consisting only of naturally occurring
amino acids, peptidomimetics or peptide analogs are also provided.
Peptide mimetics can be used to produce an equivalent or enhanced
therapeutic effect. Peptidomimetics are structurally similar to a
paradigm peptide, for example, an IL-2R.alpha. ligand that has a
biological or pharmacological activity, but have one or more
peptide linkages optionally replaced by a linkage such as
--CH.sub.2--NH--, --CH.sub.2--S--, --CH.sub.2--CH.sub.2--,
--CH.dbd.CH-- (cis and trans), --COCH.sub.2--, --CH(OH)CH.sub.2--,
and --CH.sub.2SO--, by methods known in the art.
Substitution of one or more amino acids of a consensus sequence
with a D-amino acid of the same type, such as D-lysine in place of
L-lysine, may be used to generate more stable peptides. In
addition, constrained peptides comprising a consensus sequence, or
a substantially identical consensus sequence variation may be
generated by methods known in the art; for example, by adding
internal cysteine residues capable of forming intramolecular
disulfide bridges which cyclize the peptide.
One or more amino acids of an IL-2R.alpha. ligand consensus
sequence may be replaced with a synthetic or non-naturally
occurring amino acid. Synthetic or non-naturally occurring amino
acids refer to amino acids which do not naturally occur in vivo but
which, nevertheless, can be incorporated into the peptidyl ligands
provided by the present disclosure. Suitable examples of synthetic
amino acids include the D-.alpha.-amino acids of naturally
occurring L-.alpha.-amino acid as well as non-naturally occurring
D- and L-.alpha.-amino acids represented by the formula
H.sub.2NCHRCOOH where R can be C.sub.1-6 alkyl, C.sub.3-8
cycloalkyl, C.sub.3-8 heterocycloalkyl; an aromatic residue of from
6 to 10 carbon atoms optionally having from 1 to 3 substituents on
the aromatic nucleus selected from the group consisting of
hydroxyl, lower alkoxy, amino, and carboxyl; -alkylene-Y where
alkylene is an alkylene group of from 1 to 7 carbon atoms and Y is
selected from a hydroxyl, amino, cycloalkyl, and cycloalkenyl
having from 3 to 7 carbon atoms; C.sub.6-10 aryl, such as from 1 to
3 substituents on the aromatic nucleus selected from the group
consisting of hydroxyl, lower alkoxy, amino and carboxyl;
heterocyclic of from 3 to 7 carbon atoms and 1 to 2 heteroatoms
selected from the group consisting of oxygen, sulfur, and nitrogen;
--C(O)R where R is selected from hydrogen, hydroxy, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, and --NR.sub.2 where each R is
independently selected from hydrogen and C.sub.1-4 alkyl;
--S(O).sub.nR where n is 1 or 2 and R is C.sub.1-6 alkyl and with
the proviso that R does not define a side chain of a naturally
occurring amino acid. Examples of synthetic amino acids include
amino acids wherein the amino group is separated from the carboxyl
group by more than one carbon atom such as b-alanine and
g-aminobutyric acid. Other examples of suitable synthetic amino
acids include the D-amino acids of naturally occurring L-amino
acids, L-1-naphthyl-alanine, L-2-naphthylalanine,
L-cyclohexylalanine, L-2-amino isobutyric acid, the sulfoxide and
sulfone derivatives of methionine (i.e.,
HOOC--(H.sub.2NCH)CH.sub.2CH.sub.2--S(O).sub.nR.sup.6) where n and
R.sub.6 are as defined above as well as the lower alkoxy derivative
of methionine (i.e., HOOC-- (H.sub.2NCH)CH.sub.2CH.sub.2OR where R
is C.sub.1-6 alkyl and where R does not define a side chain of a
naturally occurring amino acid).
IL-2R.alpha. ligands include bioisosteres and isosteres of the
IL-2R.alpha. ligands provided by the present disclosure.
An IL-2R.alpha. ligand provided by the present disclosure can have,
for example, less than 20 amino acids, less than 15 amino acids, or
less than 10 amino acids. For example, an IL-2R.alpha. ligand can
have from 5 to 20 amino acids, or from 10 to 15 amino acids.
IL-2R.alpha. ligands of SEQ ID NO: 1 to SEQ ID NO: 307 exhibit an
affinity (IC.sub.50) to the human IL-2R.alpha. subunit of less than
100 .mu.M.
An IL-2R.alpha. ligand provided by the present disclosure can
comprise, for example, from 5 to 50 amino acids, from 5 to 40 amino
acids, from 5 to 35 amino acids, from 5 to 30 amino acids, from 6
to 25 amino acids, or from 7 to 20 amino acids.
An IL-2R.alpha. ligand provided by the present disclosure can bind
to the human IL-2R.alpha. subunit, to a mammalian IL-2R.alpha.
subunit, or to both the human IL-2R.alpha. subunit and a mammalian
IL-2R.alpha. subunit with an IC.sub.50, for example, from 1 .mu.M
to 100 .mu.M, from 10 .mu.M to 10 .mu.M, from 100 .mu.M to 1 .mu.M,
from, 0.001 .mu.M to 1 .mu.M, or from 0.01 .mu.M to 1 .mu.M.
An IL-2R.alpha. ligand provided by the present disclosure can bind
to, for example, the human IL-2R.alpha. subunit with an IC.sub.50
from 0.1 .mu.M to 50 .mu.M.
An IL-2R.alpha. ligand provided by the present disclosure can bind
to the human IL-2R.beta. subunit and/or human IL-2R.gamma.c subunit
with an IC.sub.50, for example, of greater than 100 .mu.M, greater
than 1 mM, greater than 10 mM, or greater than 100 nM.
IL-2R.alpha. ligands and the sub-genuses of IL-2R.alpha. ligands
provided by the present disclosure do not include an IL-2R.alpha.
ligand having an amino acid sequence selected from SEQ ID NO: 308
to SEQ ID NO: 397.
TABLE-US-00026 SEQ ID NO: 308 F V R C S A N G C V SEQ ID NO: 309 S
V R C S A S G C V SEQ ID NO: 310 Y V A C S V S G C V SEQ ID NO: 311
Y V I C G A S G C V SEQ ID NO: 312 Y V R C T A I G C V SEQ ID NO:
313 F V R C S A T G C V SEQ ID NO: 314 Y V I C S A S G C V SEQ ID
NO: 315 W V R C S A S G C V SEQ ID NO: 316 F V R C S A S G C V SEQ
ID NO: 317 F V R C T A S G C V SEQ ID NO: 318 F V R C T S D G C V
SEQ ID NO: 319 Y V R C T A S G C V SEQ ID NO: 320 F R R C S A S G C
V SEQ ID NO: 321 L R R C S A N G C V SEQ ID NO: 322 L R R C S A N G
C V SEQ ID NO: 323 F V R C S L I G C V SEQ ID NO: 324 F V R C N A S
G C V SEQ ID NO: 325 F V R C T R E G C V SEQ ID NO: 326 F V R C T S
D G C V SEQ ID NO: 327 Y V I C S A S G C V SEQ ID NO: 328 F V R C T
E W G C V SEQ ID NO: 329 F V R C T A S G C I SEQ ID NO: 330 Y V R C
S E S G C V G S S W N A SEQ ID NO: 331 F V R C S E S G C V G S S W
S A SEQ ID NO: 332 Y V R C S A S G C V G S S W F L SEQ ID NO: 333 Y
V R C S D S G C V G S T W G W SEQ ID NO: 334 Y V R C S E S G C V G
S T W V F SEQ ID NO: 335 Y V R C S E S G C V G S T W V F SEQ ID NO:
336 Y V L C A L S G C V G S S W S S SEQ ID NO: 337 Y V R C G E S G
C V G S T W S T SEQ ID NO: 338 Y V R C S A T G C V G S T W T F SEQ
ID NO: 339 Y V R C G E T G C V G S T W S F SEQ ID NO: 340 Y V R C G
V S G C V G S S W V L SEQ ID NO: 341 Y V R C G E S G C V G S T W S
T SEQ ID NO: 342 F V R C S E S G C V G S S W S T SEQ ID NO: 343 Y V
R C S E S G C V G S S W W A SEQ ID NO: 344 Y V R C S V T G C V G S
S W S I SEQ ID NO: 345 Y V R C S V T G C V G S S W S I SEQ ID NO:
346 Y V R C S E S G C V G S S W S V SEQ ID NO: 347 F V R C S A D G
C V G S S W L Q SEQ ID NO: 348 Y V R C S A D G C V G S S W I T SEQ
ID NO: 349 Y V R C N P S G C V G S S W S I SEQ ID NO: 350 Y V R C S
V T G C V G S S W S I SEQ ID NO: 351 Y V R C S E S G C V G S S W S
V SEQ ID NO: 352 F V R C S A N G C V G S T W Q A SEQ ID NO: 353 Y V
R C T E S G C V G S T W T Y SEQ ID NO: 354 Y V R C S V T G C V G S
T W S V SEQ ID NO: 355 Y V R C S E I G C V G S T W S L SEQ ID NO:
356 T V R C S A T G C V G S S W V G SEQ ID NO: 357 Y V R C S A T G
C V G S S W V G SEQ ID NO: 358 F V R C S A S G C V G S S W V G SEQ
ID NO: 359 Y V R C S A D G C V G S T W N L SEQ ID NO: 360 Y V R S S
Q S G C V G S G W V L SEQ ID NO: 361 Y V A C S E S G C V G S S W S
V SEQ ID NO: 362 F V A C G E L G C V G S S W S I SEQ ID NO: 363 Y V
A C S E S G C V G S S W L A SEQ ID NO: 364 Y C R C T E S G C V G S
T W T Y SEQ ID NO: 365 F V R C T A I G C V G S S W S V SEQ ID NO:
366 Y V R C S A D G C V G S S W S A SEQ ID NO: 367 Y V R C S A S G
C V G S S W N Y SEQ ID NO: 368 Y V L C S A S G C V G S L W T H SEQ
ID NO: 369 Y V R C T D S G C V G S S W H L SEQ ID NO: 370 Y V A C S
E S G C V G S T W I T SEQ ID NO: 371 Y V A C S E S G C V G S T W T
F SEQ ID NO: 372 Y V R C G A A G C V V S S W V Y SEQ ID NO: 373 F V
R C G A S G C V G S T W G S SEQ ID NO: 374 Y V A C S E I G C V G S
T W S L SEQ ID NO: 375 Y V A C S E S G C V G S S W T W SEQ ID NO:
376 Y V A C S V S G C V G S S W S V SEQ ID NO: 377 Y V R C S E S G
C V G S T W T T SEQ ID NO: 378 Y V R C S E S G C V S S F W S A P W
K A SEQ ID NO: 379 Y V R C S E N G C V G H S W T Q G L R T SEQ ID
NO: 380 Y V R C S E S G C V S Q R P H V L E V W SEQ ID NO: 381 Y V
L C S E R G C V G Q N W A V G K L P SEQ ID NO: 382 Y V R C S E I G
C V G S H W S S Y G K H SEQ ID NO: 383 Y V R C S E N G C V G S S W
G R V T L D SEQ ID NO: 384 Y V R C S E S G C V G C E L V W Y F I T
SEQ ID NO: 385 Y V R C S E S G C V G S S W G A V A S I SEQ ID NO:
386 Y V R C S E S G C V G S S W G A V A S I SEQ ID NO: 387 Y V R C
S E S G C V G S S W S V S P R G SEQ ID NO: 388 Y V R C G E S G C V
S S S W S T M G N S SEQ ID NO: 389 Y V R C S E N G C V G S S W E H
S A I I SEQ ID NO: 390 Y V R C S E G G C V G S T W T A S Y P N SEQ
ID NO: 391
Y V R C S E S G C V G S T W N G V L S R SEQ ID NO: 392 Y V R C S E
S G C V G S T W N G V L S R SEQ ID NO: 393 T V R C S Q S G C V G C
Q L V W Y F T T SEQ ID NO: 394 Y V N C S Q S G C V G S T W N G V F
S N SEQ ID NO: 395 Y V A C S E S G C V S V D S S A G A L F SEQ ID
NO: 396 Y V R C N E T G C V G S S W I A A G P F SEQ ID NO: 397 Y V
R C S E S G C V G S T W L F N P W G
Compounds provided by the present disclosure comprise at least one
IL-2R.alpha. ligand. Compounds can comprise, for example, from 1 to
10 IL-2R.alpha. ligands, from 1 to 6 IL-2R.alpha. ligand, or from 1
to 3 IL-2R.alpha. ligands. Examples of compounds comprising at
least one IL-2R.alpha. ligand include peptides and conjugates.
Examples of conjugates include one or more IL-2R.alpha. ligands
bound to a polypeptide, a macromolecule such as a polyethylene
glycol, a fusion protein, or a biological molecule such as an
antibody.
Functionally, compounds comprising at least one IL-2R.alpha. ligand
can be IL-2R.alpha..beta..gamma.c agonists, IL-2R.alpha.
antagonists, IL-2R.alpha..beta. antagonists,
IL-2R.alpha..beta..gamma.c antagonists, IL-2R.alpha..beta..gamma.c
antagonists, diagnostic reagents, imaging reagents, targeting
compounds, cytotoxic compounds, and compounds exhibiting dual
pharmacology.
Compounds comprising an IL-2R.alpha. ligand provided by the present
disclosure can have a molecular weight, for example, from 1,000 to
400,000 Da, from 1,000 to 200,000 Da, from 1,000 to 100,000 Da,
from 1,000 Da to 20,000 Da, from 1,500 Da to 15,000 Da, from 2,000
Da to 10,000 Da, or from 5,000 Da to 10,000 Da.
Compounds comprising an IL-2R.alpha. provided by the present
disclosure can be attached to one or more moieties that impart a
property to the compound that enhances therapeutic efficacy.
Examples of properties include potency, aqueous solubility,
polarity, lipophilicity, pharmacokinetics, targeting,
bioavailability, pH-dependent binding, bioactivity,
pharmacodynamics, cellular activity, metabolism, efficacy,
reversible incapacitation (caging), selectivity, or a combination
of any of the foregoing.
Compounds comprising an IL-2R.alpha. ligand can comprise one or
more moieties that are cleavable in vivo. The moiety can be
cleavable in a target specific environment such as, for example, by
a target specific or target enriched enzyme, or pH. The moiety can
be cleavable upon exposure to electromagnetic energy such as
visible light or infrared radiation and/or by exposure to thermal
energy.
Compounds comprising an IL-2R.alpha. ligand can include a polymer,
a peptide, an antibody.
Compounds comprising an IL-2R.alpha. ligand can include a
tumor-targeting moiety such as, for example, a tumor-specific
antibody, a tumor-specific antibody fragment, a tumor-specific
protein, a tumor-specific peptide, a non-peptidyl tumor cell
ligand, or a combination of any of the foregoing.
Compounds comprising an IL-2R.alpha. ligand can comprise a caged
molecule or molecules. A caged molecule can in effect encapsulate
the compound and can serve to prevent bioactivity in certain
tissues, for example, to protect peripheral tissues from the
toxicity of IL-2R.alpha..beta..gamma.c activation.
Compounds comprising an IL-2R.alpha. ligand can comprise a moiety,
wherein the moiety comprises a small molecule, a peptide, a
polymer, or an antibody. The small molecule can be a non-peptidyl
molecule. The moiety can exhibit a pharmacological effect. The
pharmacological effect can manifest when the moiety is bound to the
IL-2R.alpha. and/or after the moiety is cleaved from the compound
comprising an IL-2R.alpha. ligand.
Compounds comprising an IL-2R.alpha. ligand can comprise a moiety
configured to sustain a circulating reservoir of the compound
comprising an IL-2R.alpha. ligand.
Compounds comprising an IL-2R.alpha. ligand can comprise a moiety
configured to target the IL-2R-directed immuno-stimulation of the
effector immune cells in the tumor.
Compounds comprising an IL-2R.alpha. ligand can comprise a moiety
configured to target specific immune cells such as Treg cells.
The moiety can comprise a compound that is toxic to a cell targeted
by the compound comprising an IL-2R.alpha. ligand. A compound
comprising an IL-2R.alpha. ligand can target cells having a high
expression level of the IL-2R.alpha. subunit such as Treg cells and
the compound can comprise a moiety toxic to the cells expressing
the IL-2R.alpha. subunit such as Treg cells. The toxic moiety can
be cleavable or otherwise activated such as by exposure to
electromagnetic radiation. The toxic moiety can be activated by
exposure to electromagnetic radiation.
Compounds comprising an IL-2R.alpha. ligand provided by the present
disclosure can activate the IL-2 receptor. Compounds comprising an
IL-2R.alpha. ligand provided by the present disclosure can inhibit
the IL-2 receptor. Certain compounds comprising an IL-2R.alpha.
ligand provided by the present disclosure can bind to the
IL-2.alpha. subunit and prevent other compounds from binding to the
IL-2.alpha. subunit. Compounds comprising an IL-2R.alpha. ligand
can reduce the potency of or interfere with the binding of IL-2R
agonists to cells that highly express the IL-2R.alpha. ligand.
Compounds comprising an IL-2R.alpha. ligand can reduce the
sensitivity of Treg cells to IL-2.
Peptides provided by the present disclosure include at least one
IL-2R.alpha. ligand. A peptide can include, for example, less than
50 amino acids, which include the amino acids constituting the
IL-2R.alpha. ligand.
A peptide comprising an IL-2R.alpha. ligand can comprise, for
example, from 5 to 100 amino acids, from 5 to 80 amino acids, from
5 to 50 amino acids, from 10 to 40 amino acids, from 10 to 30 amino
acids, or from 15 to 25 amino acids.
In addition to an IL-2R.alpha. ligand, a peptide can include
additional amino acids, for example, for establishing the
conformation of an IL-2R.alpha. ligand and/or for coupling the
IL-2R.alpha. ligand to other compounds. The additional amino acids
can be bonded to the N-terminus and/or to the C-terminus of the
IL-2R.alpha. ligand.
Conjugates provided by the present disclosure include at least one
IL-2R.alpha. ligand.
A conjugate can comprise a polypeptide.
A polypeptide can be a single chain tandem peptide having two more
IL-2R.alpha. ligands. The IL-2R.alpha. ligands can be bonded
through amino acid linkers.
An amino acid linker can comprise, for example, more than one amino
acid, greater than 5 amino acids, greater than 10 amino acids,
greater than 50 amino acids, or greater than 100 amino acids. A
peptide linker can comprise, for example, from 1 to 100 amino acids
from 3 amino acids to 75 amino acids, from 5 amino acids to 50
amino acids, or from 10 amino acids to 25 amino acids.
For example, in a homodimer, the C-terminus of a first IL-2R.alpha.
ligand and the C-terminus of a second IL-2R.alpha. ligand can be
attached to the linker; the N-terminus of a first IL-2R.alpha.
ligand and the N-terminus of a second IL-2R.alpha. ligand can be
attached to the linker; or the C-terminus of a first IL-2R.alpha.
ligand and the N-terminus of a second IL-2R.alpha. ligand can be
attached to the linker.
A polypeptide comprising an IL-2R.alpha. ligand provided by the
present disclosure can comprise, for example, from 5 amino acids to
4,000 amino acids, from 5 amino acids to 3,000 amino acids, from 5
amino acids to 2,500 amino acids, or from 5 amino acids to 2,000
amino acids.
A polypeptide can be a synthetic peptide or a recombinant
polypeptide.
A single chain tandem peptide can be a heteromer having at least
one IL-2R.alpha. ligand in combination with one or more IL-2R.beta.
ligands and/or one or more IL-2R.gamma.c ligands. For example, a
single chain tandem peptide can comprise an IL-2R.alpha. ligand, an
IL-2R.beta. ligand, and an IL-2R.gamma.c ligand with amino acid
linkers coupling adjacent ligands. A single chain tandem peptide
can further include additional amino acids at the N-terminus and/or
C-terminus of the polypeptide.
The IL-2R.alpha. and IL-2R.beta. ligand and/or IL-2R.gamma.c ligand
can be arranged in any order.
Each of the adjacent ligands can independently be coupled through
the N-terminus of each ligand, through the C-terminus of each
ligand, through the N-terminus and C-terminus of the adjacent
ligands, or through the side chains of the ligands and/or
linkers.
For example, in a heteromer, the C-terminus of an IL-2R.alpha.
ligand can be attached to the linker and the N-terminus of an
IL-2R.beta. ligand or the N-terminus of an IL-2R.gamma.c ligand can
be attached to the linker; the C-terminus of an IL-2R.beta. ligand
or the N-terminus of an IL-2R.gamma.c ligand can be attached to the
linker, or the N-terminus of an IL-2R.alpha. ligand can be attached
to the linker. Other examples of suitable linkers include DIG,
PEG13, PEG25, PEG1K, PEG2K, PEG3.4K, PEG4K, PEG5K, IDA, IDA-Palm,
IDA-Boc, IDA-Ac, IDA-Isovaleric acid, ADA triazine, triazine-Boc,
isophthalic acid, 1,3-phenylenediacetic acid, Glu, Asp, D-Glu,
D-Asp, 1,4-phenylenediacetic acid, biphenyl diacetic acid,
cyclopropylacetic acid, succinic acid, glutaric acid, dodecanedioic
acid, suitable aliphatic diacids, suitable aromatic diacids,
heteroaromatics, and polyethylene glycols having a molecular
weight, for example, from 400 Da to 40,000 Da.
The individual IL-2R.alpha. ligands can be linked in various ways
to produce homodimers or homomers, heteromers, that can be
evaluated for IL-2R agonist and/or IL-2R antagonist activity. For
example, homodimers of IL-2R.alpha. ligands or heteromers of an
IL-2R.alpha. ligand with IL-R.beta. ligand and/or IL-2R.gamma.c
ligand can function as an IL-2R antagonist. Agonist and antagonist
activity can depend on heteromers binding simultaneously to both
IL-2R.beta. and IL-2R.gamma.c subunits to induce proximity and
orientation compatible with signaling or inhibition. Several
compound characteristics can influence the activity of homodimers
or heteromers such as, for example, the linker structure, the
linker length, the peptide ligand orientation, the ECD binding
site-specificity of the monomeric peptides, and the affinities of
each ligand for the respective receptor subunits. IL-2R agonist and
IL-2R antagonist activity can depend on increasing the affinity of
the IL-2R.alpha. ligand to the IL-2R.alpha. subunit. Induced
receptor subunit orientation and the potential for proper
intra-cellular alignment and signaling can be, in part, a function
of the orientations in which the peptide ligands link to form the
heteromer. To determine suitable induced subunit orientations,
adjacent IL-2R ligands can be linked in any of four (4) possible
orientations such that the C-termini of both subunit binding
ligands are coupled through a linker, the N-termini of both subunit
binding ligands are coupled through a linker, or the N-terminus of
one binding subunit can be bound through the C-terminus of the
other binding subunit through a suitable linker. Homomers and
heteromers can also be linked through amino acid side chains.
Heteromer linkage orientation can be engineered, for example, by
synthesizing ligand monomers with the click functionality, i.e.,
azide or alkyne, and PEG-linker on either the N-terminus or on the
C-terminus.
A polypeptide can be a synthetically modified polypeptide
comprising one or more IL-2R.alpha. ligands. The modifications can
be influence, for example, the activity of the polypeptide or the
pharmacokinetics of the polypeptide. Examples include polypeptides
incorporating polyethylene glycol moieties or albumin binding
moieties.
Compounds comprising an IL-2R.alpha. ligand can be a fusion protein
where the fusion partner is from a biological source. An
IL-2R.alpha. ligand can be fused to another protein that imparts a
desired functionality to the construct. For example, the protein
can impart a desired pharmacokinetic profile or to target specific
antigens.
Examples of suitable fusion partners include Fc fusion proteins,
IgG fusion proteins, human serum albumin (HSA) fusion proteins,
other human proteins and mutants and/or variants thereof; and
hydrophilic, biodegradable protein polymers. A fusion protein
partner can be a naturally occurring protein, a modified-naturally
occurring protein, or a synthetic protein.
For example, an IL-2R.alpha. ligand provided by the present
disclosure can be fused to a protein that increases the circulating
half-life of the compound. Fusion of therapeutic proteins with IgG
or IgG Fc domains accomplishes this by increasing the hydrodynamic
radius of the protein, thus reducing renal clearance, and through
Neonatal Fc Receptor (FcRn)-mediated recycling of the fusion
protein, and thereby prolonging the circulating half-life. Other
fusion proteins can be designed to modify properties such as the
pharmacokinetics, biodistribution, pharmacodynamics, pharmacology,
cytotoxicity, and/or targeting.
A fusion protein provided by the present disclosure can comprise a
peptide, or multiple tandem peptides provided by the present
disclosure linked to one or more fusion protein partners. A fusion
protein partner can be linked to the N-terminus and/or the
C-terminus of tandem peptides. One or more fusion protein partners
can be linked to the N-terminus and/or the C-terminus of tandem
peptides. An IL-2R.alpha. ligand can be linked to one or more
fusion protein partners, where each of the fusion protein partners
can be the same or some of the fusion protein partners can be
different than other of the fusion protein partners linked to a
peptide.
The amino acid sequence at the junction between an IL-2R.alpha.
ligand and a fusion partner protein can be either a direct fusion
of the two protein sequences or a fusion with an intervening linker
peptide. Linker peptides can be included as spacers between the two
protein moieties. Linker peptides can promote proper protein
folding and stability of the component protein moieties, improve
protein expression, and enable better bioactivity of the component
protein moieties. Peptide linkers used in fusion proteins can be
designed to be unstructured flexible peptides. Peptide linkers can
be, for example, rich in glycine and serine, such as repeats of a
sequence such as, for example, GS, GGS, GGGS (SEQ ID NO: 1039), or
GGGGS (SEQ ID NO: 1040). A flexible linker peptide with a fully
extended .beta.-strand conformation can have an end-to-end length
of approximately 3.5 .ANG. per residue. Thus, a linker peptide of
5, 10, 15, 20 or more than 20 residues can have a maximum fully
extended length of 17.5 .ANG., 35 .ANG., 52.5 .ANG., 70 .ANG., 140
.ANG., or more than 140 .ANG., respectively.
A linker peptide can facilitate obtaining an appropriate
conformation and orientation of individual fusion protein moieties
to facilitate the engagement of the IL-2R.alpha. ligand with the
IL-2R.alpha. subunit, facilitate binding of the IL-2R.alpha. ligand
to the IL-2 receptor, enable fusion protein recycling, and prolong
the circulating half-life of the active moiety. Because the factors
influencing these interactions are difficult to predict, the
requirement for and the proper length of a linker peptide must be
empirically tested and determined.
There are multiple options for the design and construction of a
fusion protein comprising an IL-2R.alpha. ligand and which can be
selected to obtain a compound having the desired biological
activity and pharmaceutical characteristics. Design options
include, for example, the nature of the IL-2R.alpha. ligand, the
choice of the fusion partner protein moiety, the configuration of
fusion partners in the fusion protein, and the amino acid sequence
at the junction between the IL-2R.alpha. ligand and the fusion
partner protein.
In general, preparation of the fusion proteins provided by the
present disclosure can be accomplished by recognized recombinant
DNA techniques involving, for example, polymerase chain
amplification reactions (PCR), preparation of plasmid DNA, cleavage
of DNA with restriction enzymes, preparation of oligonucleotides,
ligation of DNA, isolation of mRNA, introduction of the DNA into a
suitable cell, transformation or transfection of a host, culturing
of the host. Additionally, fusion proteins can be isolated and
purified using chaotropic agents and well known electrophoretic,
centrifugation and chromatographic methods.
Genes encoding fusion proteins provided by the present disclosure
involve restriction enzyme digestion and ligation as the basic
steps employed to yield DNA encoding the desired fusions. The ends
of the DNA fragment may require modification prior to ligation, and
this may be accomplished by filling in overhangs, deleting terminal
portions of the fragment(s) with nucleases (e.g., ExoIII), site
directed mutagenesis, or by adding new base pairs by PCR.
Polylinkers and adaptors can be employed to facilitate joining of
selected fragments. The expression construct can be assembled in
stages employing rounds of restriction, ligation, and
transformation of E. coli. Numerous cloning vectors suitable for
construction of the expression construct are known in the art. The
selection of a cloning vector can be influenced by the gene
transfer system selected for introduction of the expression
construct into the host cell. At the end of each stage, the
resulting construct may be analyzed by restriction, DNA sequence,
hybridization and PCR analyses.
Site-directed mutagenesis can be used to introduce specific
mutations into the genes encoding the fusion proteins provided by
the present disclosure.
Various promoters (transcriptional initiation regulatory region)
may be used. The selection of the appropriate promoter can depend
on the proposed expression host. Promoters from heterologous
sources may be used as long as they are functional in the chosen
host.
Various signal sequences may be used to facilitate expression of
the fusion proteins. Signal sequences can be selected or designed
for efficient secretion and processing in the expression host may
also be used. A signal sequence which is homologous to the human
IL-2 coding sequence may be used for mammalian cells. The signal
sequence may be joined directly through the sequence encoding the
signal peptidase cleavage site to the protein coding sequence, or
through a short nucleotide bridge.
Nucleic acids encoding a desired fusion protein can be introduced
into a host cell by standard techniques for transfecting cells.
Alternatively, one can use synthetic gene construction for all or
part of the construction of the fusion proteins. This can entail in
vitro synthesis of a designed polynucleotide molecule to encode a
polypeptide molecule of interest. Gene synthesis can be performed
utilizing a number of techniques, such as the multiplex
microchip-based technology and similar technologies wherein
oligonucleotides are synthesized and assembled upon
photo-programmable microfluidic chips.
Fusion proteins provided by the present disclosure can be isolated
from harvested host cells or from the culture medium.
Compounds comprising an IL-2R.alpha. ligand provided by the present
disclosure include compounds that act as IL-2R.alpha..beta..gamma.c
agonists.
An IL-2R.alpha..beta..gamma.c agonist provided by the present
disclosure can comprise synthetic peptides or recombinant peptides
linked in tandem to create a single chain peptide comprising an
IL-2R.alpha. ligand, an IL-2R.beta. ligand, and an IL-2R.gamma.c
ligand. The ligands can be in any order and can be separated by
amino acid linkers. The synthetic peptides can comprise natural
amino acids or peptides with natural amino acids and suitable
substitutions with unnatural amino acids.
IL-2R.alpha..beta..gamma.c agonists provided by the present
disclosure can be a recombinant fusion protein comprising an
IL-2R.alpha. ligand, an IL-2R.beta. ligand, and IL-2R.gamma.c
ligand and fusion partner such as an Fc protein, an IgG protein,
human serum albumin or other natural or designed protein, or a
hydrophilic, biodegradable protein polymer. An
IL-2R.alpha..beta..gamma.c agonist can comprise one or more
IL-2R.alpha. ligands. An IL-2R.alpha..beta..gamma.c agonist can
comprise an IL-2R.alpha. ligand, an IL-2R.beta. ligand, and an
IL-2R.gamma.c ligand and include one or more moieties selected to
modify the pharmacokinetics of the IL-2R.alpha..beta..gamma.c
agonist such as PEG or an albumin binding moiety.
An IL-2R.alpha..beta..gamma.c agonist can bind to IL-2R.alpha. and
activate the IL-2 receptor. An IL-2R.alpha..beta..gamma.c agonist
can bind to IL-2R.alpha. with an IC.sub.50, for example, less than
100 .mu.M, less than 10 .mu.M, less than 1 .mu.M, less than 100 nM,
less than 10 nM, or less than 1 nM. An IL-2R.alpha..beta..gamma.c
agonist can bind to IL-2R.alpha. either competitively or
non-competitively with IL-2.
An IL-2R.alpha..beta..gamma.c agonist comprising an IL-2R.alpha.
ligand, an IL-2R.beta. ligand, and an IL-2R.gamma.c ligand can be
configured to more potently activate cells expressing the
IL-2R.alpha. subunit, thereby facilitating the ability to
differentially activate IL-2R expressed on the surface of different
cell types by controlling dose of the agonist. For example, when
incubated with a heteromeric compound comprising an IL-2R.alpha.
ligand, IL-2R.beta. ligand, and an IL-2R.gamma.c ligand, primary
human peripheral blood mononuclear cells (PBMC) expressing the
IL-2R.alpha..beta..gamma.c subunit, phosphorylate transcription 5
(STAT5) under conditions wherein human peripheral blood mononuclear
cells (PBMC) expressing only the IL-2R.beta..gamma.c subunits, do
not phosphorylate transcription 5 (STAT5) to the same degree. A
heteromer can comprise an IL-2R.alpha. ligand, IL-2R.beta. ligand,
an IL-2R.gamma.c ligand, and a linker, where the linker is
configured such that the heteromer is an agonist for the IL-2
receptor. A linker can comprise a length that facilitates binding
of an IL-2R.alpha. ligand, an IL-2R.beta. ligand, and an
IL-2R.gamma.c ligand to the IL-2 receptor. For example, a linker
can have a length from 10 .ANG. to 400 .ANG., from 10 .ANG. to 300
.ANG., from 10 .ANG. to 200 .ANG., 20 .ANG. to 100 .ANG., from 30
.ANG. to 80 .ANG., or from 40 .ANG. to 60 .ANG.. A linker can
comprise a chemical structure that facilitates simultaneous binding
of an IL-2R.alpha. ligand, an IL-2R.beta. ligand, an IL-2R.gamma.c
ligand to the respective IL-2 receptor subunits. For example, a
linker can comprise a peptide or a hydrocarbon.
An IL-2R.alpha..beta..gamma.c agonist can partially activate the
IL-2 receptor. Partial activation refers to a level of activation,
that is, for example, less than 75% of maximum activation, less
than 50%, less than 25%, less than 10%, or less than 1% of the
maximum activation. Maximum activation (E.sub.max) is the amplitude
of cellular signal (activation) achievable at high agonist
concentration such as a high concentration of IL-2. Partial
IL-2R.alpha..beta..gamma.c agonists can be effective in modulating
the levels of response of IL-2R to activation by the IL-2R.beta.
and IL-2R.gamma.c subunits among different cell types expressing
IL-2R. For example, different cell types are known to vary in
expression levels of each of the IL-2R subunits, R.alpha., R.beta.,
and Rye, and to exhibit different sensitivities to IL-2R
agonists.
An IL-2R agonist comprising one or more IL-2R.alpha. ligands can
exhibit increased binding and potency on cells expressing the
IL-2R.alpha. subunit (such as Tregs). Natural IL-2R agonists, or
mutants and modified forms of natural IL-2R agonists such as IL-2,
can be modified to include additional IL-2R.alpha. ligands to
further increase affinity and potency of these agonists on
IL-2R.alpha. expressing cells.
An IL-2R.alpha..beta..gamma.c agonist can comprise an IL-2R.alpha.
ligand and modified IL-2R.beta. and/or IL-2R.gamma.c ligands.
Modified IL-2R.beta. and IL-2R.gamma.c ligands can be selected or
designed to bind and activate IL-2R, but with low or modest
affinity and potency to IL-2R. Such IL-2R.alpha..beta..gamma.c
agonists can have greater differential sensitivity for IL-2R
activation between cells that highly express IL-2R.alpha. and cells
having a low level of IL-2R.alpha. expression. For examples,
between Tregs that have a high expression of IL-2R.alpha. and Teff
cells that have a low expression level of IL-2R.alpha..
An IL-2R.alpha..beta..gamma.c agonist can comprise one or more
IL-2R.alpha. ligands. The presence of multiple IL-2R.alpha. ligands
can preferentially increase the potency of the agonists on cells
that highly express IL-2R.alpha. compared to cells having low
expression levels of IL-2R.alpha..
An IL-2R.alpha..beta..gamma.c agonist can comprise a moiety having
an additional pharmacological activity other than that mediated by
activation of the IL-2 receptor. The pharmacological activity can
be an activity that has a therapeutic efficacy that is synergistic
with that of the IL-2R.alpha..beta..gamma.c agonist or the
pharmacological activity can be an activity that has a therapeutic
efficacy that is not synergistic with that of the
IL-2R.alpha..beta..gamma.c agonist. For example, a moiety or
molecule having a useful pharmacological activity can comprise a
checkpoint inhibitor.
Compounds provided by the present disclosure include IL-2R.alpha.
antagonists. An IL-2R.alpha. antagonist is a compound comprising an
IL-2R.alpha. ligand that inhibits binding of IL-2 and mutants and
modified forms thereof, to the IL-2R.alpha. subunit and/or
diminishes IL-2 activation of the IL-2 receptor.
IL-2R.alpha. antagonists can attenuate the sensitivity of cells
expressing the IL-2R.alpha. subunit to activation by IL-2 or
mutants and modified forms thereof. Examples of cells expressing
the IL-2R.alpha. subunit include Tregs.
IL-2R.alpha. antagonists include compounds having more than one
IL-2R.alpha. ligand and can bind competitively or non-competitively
with IL-2 to the IL-2 receptor.
IL-2R.alpha. antagonists can comprise one or more IL-2R.alpha.
ligands and a moiety having a useful pharmacological activity. The
moiety can exhibit a pharmacological activity that is synergistic
with IL-2R.alpha. inhibition or is not synergistic with inhibition
of the IL-2R.alpha. subunit.
IL-2R.alpha. antagonists further include recombinant fusion
proteins.
An IL-2R antagonist can comprise an IL-2R.alpha. ligand only; an
IL-2R.alpha. ligand and an IL-2R.beta. ligand; an IL-2R.alpha.
ligand and an IL-2R.gamma.c ligand; or an IL-2R.alpha. ligand, an
IL-2R.beta. ligand, and an IL-2R.gamma.c ligand.
IL-2R antagonists include compounds that bind to either the
IL-2R.alpha. subunit or to the IL-2R.beta. or IL-2R.gamma.c subunit
and inhibit activation of the IL-2 receptor.
IL-2R antagonists include compounds that bind to the IL-2R.alpha.
subunit and to the IL-2R.beta. and/or the IL-2R.gamma.c subunits
and inhibit activation of the IL-2 receptor, where the IL-2R.beta.
and IL-2R.gamma.c ligands are configured to not activate the IL-2
receptor. Such compounds are high affinity antagonists for IL-2R
activation and the presence of an IL-2R.alpha. ligand enhances the
potency of the IL-2R antagonists.
IL-2R antagonists include compounds comprising the IL-2R.alpha.
and/or the IL-2R.beta. and/or the IL-2R.gamma.c ligands, which are
configured to exhibit partial activation of the IL-2 receptor.
These compounds are examples of partial IL-2R agonists. Such
compounds are useful for modulating the level of response of cells
to IL-2R agonists among cells having different expression levels of
IL-2R subunits. Use of the partial IL-2R agonists/antagonists can
modulate the response of cells to IL-2R agonists among cells having
different expression levels of the IL-2R.alpha., IL-2R.beta.,
and/or IL-2R.gamma.c subunits.
An IL-2R antagonist can comprise one or more IL-2R.alpha. ligands.
An IL-2R antagonist can be a peptide or a polypeptide, which can be
synthetic or recombinant. In addition to one or more IL-2R.alpha.
ligands, an IL-2R antagonist can comprise one or more IL-2R.beta.
ligands and/or one or more IL-2R.gamma.c ligands. The IL-2R ligands
can be coupled in any order, in any orientation, and can be coupled
with linkers. The linkers can comprise natural and/or unnatural
amino acids and/or non-peptidyl structures.
A peptidyl or polypeptidyl IL-2R antagonist can be chemically
modified to include, for example, moieties that affect the
pharmacokinetics of the IL-2R antagonist such as PEG and
albumin-binding moieties.
IL-2R antagonists further include recombinant fusion proteins.
Compounds comprising an IL-2R.alpha. ligand include diagnostic
reagents. As a diagnostic agent, a compound comprising an
IL-2R.alpha. ligand can be used to detect and/or measure cells
expressing the IL-2R.alpha. ligand. The compounds can be used to
determine the expression level of the IL-2R.alpha. expression of a
cell, or population of cells, or of a tissue. The compounds can be
used to assess the binding affinity of the IL-2R.alpha. subunits in
a cell or population of cells. The compounds may be used to
determine the type of cell, for example, based on IL-2R.alpha.
expression levels.
The compounds can be useful for in vitro and in vivo
diagnostics.
A diagnostic compound comprising an IL-2R.alpha. ligand can
comprise a detectable marker. The detectable marker can be
cleavable or non-cleavable.
A detectable marker can comprise, for example, a radiolabel, a
fluorescent label, an enzymatic label.
A diagnostic compound comprising an IL-2R.alpha. ligand can be used
to measure cells expressing the IL-2R.alpha. subunit and/or the
level of expression of cells expressing the IL-2R.alpha. subunit in
a biological sample such as a sample of blood of a patient.
Measurements can be made, for example, using flow cytometry. The
number of cells expressing the IL-2R.alpha. subunit and/or the
expression level of the IL-2R.alpha. subunit, when correlated with
a disease in a patient or a pharmacologically significant parameter
of the disease in a patient can be used to inform treatment of the
disease. For example, if a level of expression of the IL-2R.alpha.
subunit is above or below a therapeutically meaningful threshold
for a particular disease, a compound comprising an IL-2R.alpha.
ligand provided by the present disclosure can be administered to
the patient to treat the disease.
Compounds comprising an IL-2R.alpha. ligand can be attached to a
solid support. Based on their ability to bind to the IL-2R.alpha.
subunit, the compounds can be used as reagents for detecting
IL-2R.alpha. subunits, for example, on living cells, fixed cells,
in biological fluids, in tissue homogenates, in purified, and
natural in biological materials. In addition, based on their
ability to bind the IL-2R.alpha. subunit, the peptides of the
present invention can be used, for example, in in situ staining,
FACS (fluorescence-activated cell sorting), Western blotting, and
ELISA. In addition, compounds provided by the present disclosure
can be used in receptor purification, or in purifying cells
expressing IL-2R.alpha. subunit on the cell surface.
Compounds comprising an IL-2R.alpha. ligand provided by the present
disclosure can also be used as reagents for various medical
research and diagnostic uses. Such uses include, for example, use
as a calibration standard for quantitating the activities of
candidate IL-2R agonists or IL-2R antagonists in functional assays;
use to maintain the proliferation and growth of IL-2-dependent cell
lines; (3) use in structural analysis of the IL-2-receptor through
co-crystallization; use to investigate the mechanism of IL-2 signal
transduction/receptor activation; and other research and diagnostic
applications wherein the IL-2-receptor is implicated.
Assessing single patient response to therapy and qualifying a
patient for optimal therapy are among the greatest challenges of
modern healthcare and relate to trends in personalized medicine. A
compound comprising an IL-2R.alpha. ligand can have target
selectivity for diseases in which cells associated with the
etiology of the disease express the IL-2R.alpha. ligand. For
example, a compound comprising an IL-2R.alpha. ligand radiolabeled
for positron emission tomography (PET) or single photon emission
computed tomography (SPECT) can be used to predict the targeting of
the treatment based on a single-study, case-by-case patient
analysis thus excluding subjects that are expected not to benefit
from treatment with a therapeutic compound affecting the activity
of the IL-2R.alpha. subunit. PET/SPECT scans using radiolabeled a
compound comprising an IL-2R.alpha. ligand, once correlated to the
concentration of a compound comprising an IL-2R.alpha. ligand can
provide a three-dimensional distribution map, which can then be
used for macroscopic dose calculations.
Compounds comprising an IL-2R.alpha. ligand can comprise one or
more imaging agents. The IL-2R.alpha. ligand can direct and
localize the compound to cells, populations of cells, and tissue
expressing the IL-2R.alpha. subunit. The imaging compounds can
comprise one or more imaging agents such as radiolabels,
fluorescent labels, enzymatic labels, or PET imaging agents.
The imaging agents can be used to determine the number of cells
expressing the IL-2R.alpha. subunit, the expression level of cells
expressing the IL-2R.alpha. subunit, or properties of the
IL-2R.alpha. subunit such as the affinity of the IL-2R.alpha.
subunit to a particular IL-2R.alpha. ligand and/or compound
comprising an IL-2R.alpha. ligand. The imaging agents can be used,
for example, to evaluate cancer cells expressing the IL-2R.alpha.
receptor, or to evaluate Treg and/or Teff cells.
The label can be detected to determine a biodistribution of the
compound in a patient or to assess the potential for therapeutic
efficacy. For examples, tumors expressing high levels of the IL-2R
receptor and/or the IL-2R.alpha. subunit may be attractive targets
for compounds comprising an IL-2R.alpha. ligand provided by the
present disclosure.
The imaging agents can be used to evaluate cells expressing the
IL-2R.alpha. subunit before therapy, during therapy, and/or
following therapy.
Imaging agents comprising an IL-2R.alpha. ligand can further
comprise a moiety capable of binding to a cell surface and in
particular to a protein expressed on the cell surface. The protein
can be indicative of a certain cell type and is referred to as a
cell surface marker. Imaging agents comprising both an IL-2R.alpha.
ligand and a cell surface marker can be used to assess cells, a
population of cells, and/or a tissue expressing both the
IL-2R.alpha. subunit and the cell surface marker. Assessment can
include determining the number of cells expressing both the
IL-2R.alpha. subunit and the cell surface marker, the expression
levels of the IL-2R.alpha. subunit and the cell surface marker,
and/or the affinity of the imaging agent to the IL-2R.alpha.
subunit and/or the cell surface marker.
Cells expressing both the IL-2R.alpha. subunit and the cell surface
marker can be, for example, Tregs and/or activated Teff cells.
The imaging agents can be used to evaluate cells expressing the
IL-2R.alpha. subunit and the cell surface marker before therapy,
during therapy, and/or following therapy.
As a practical example, T cell infiltration of tumor lesions is a
known prognostic factor in several tumor types and is used as a
treatment mechanism in some of these tumor types. For example, in
metastatic melanoma, treatment with immune checkpoint inhibitors
induces clinical benefit in about 30-50% of the patients.
Tumor-infiltrating T cells express the IL-2 receptor on their
surface. Therefore, these T cells can be visualized by molecular
imaging with a compound comprising an IL-2R.alpha. ligand and a
radiolabel such as a PET tracer.
As another example, IL-2 is synthesized and secreted by activated T
lymphocytes, especially CD8.sup.+ CTL and CD4.sup.+ Th1
lymphocytes. T lymphocyte activation is observed in many types of
inflammatory diseases, such as inflammatory degenerative diseases,
graft rejection, tumor inflammation, organ-specific autoimmune
diseases, and adipose inflammatory insulin resistance. IL-2 binds
with high affinity to the cell membrane IL-2 receptor, which is
mainly expressed on the cell surface of activated T lymphocytes.
PET imaging of activated T lymphocytes by a radiolabeled compound
comprising an IL-2R.alpha. ligand therefore provides an in vivo,
dynamic approach in studying the immune-cell infiltration in these
inflammatory diseases.
Compounds comprising IL-2R.alpha. ligands can comprise a
cell-specific targeting moiety or molecule.
A cell-specific targeting moiety can comprise a moiety that has an
affinity for a component on the surface of a cell such as a
receptor, a protein, or an epitope. A moiety can comprise, for
example, a ligand or an antibody having an affinity to a cell
surface component.
The targeting moiety can direct and concentrate compounds
comprising an IL-2R.alpha. ligand at the cells, population of
cells, or tissue targeted by the targeting moiety.
The targeting moiety can enhance the potency of IL-2R agonism or
IL-2R antagonism for the cells or population of cells being
targeted.
The targeting moiety can provide a differential response to IL-2R
agonism or to IL-2R antagonism between the cells being targeted and
the cells not being targeted by the targeting moiety.
The targeting moiety can provide a differential response to IL-2R
agonism or IL-2R antagonism between cells having a high expression
level of the targeted component and cells having a lower expression
level of the targeted component.
Compounds comprising an IL-2R.alpha. ligand can further comprise a
bioactive moiety or a bioactive molecule. A compound comprising an
IL-2R.alpha. ligand can be used to deliver the bioactive moiety or
bioactive molecule to cells, to a population of cells, or to a
tissue expressing the IL-2R.alpha. subunit.
The bioactive moiety or molecule can be non-cleavable and capable
of exerting a biological activity when bound to the compound
comprising an IL-2R.alpha. ligand.
The bioactive moiety or molecule can be cleavable. The moiety can
be cleavable by any suitable mechanism such as by pH, enzymatic,
thermal, and/or electromagnetic mechanisms. Electromagnetic
mechanisms include, for example, exposing the compounds to
infrared, visible, or ultraviolet radiation, where the bioactive
moiety is attached to the compounds comprising an IL-2R.alpha.
ligand through a photolabile moiety capable of being cleaved by the
radiation.
The bioactive molecule can be non-cleavable but otherwise
activatable, such as for example, activatable by exposure to
electromagnetic radiation.
IL-2R.alpha. ligands can be selected to have enhanced binding to
the IL-2R.alpha. subunit at a certain pH. For example, a
pH-selective IL-2R.alpha. ligand can have a greater affinity to the
IL-2R.alpha. subunit at low pH commensurate with that of a solid
tumor microenvironment. Compounds comprising low-pH selective
IL-2R.alpha. ligands can be used to preferentially target cells in
low pH environments expressing the IL-2R.alpha. subunit compared to
cells in normal pH environments associated with healthy tissue.
Thus, compounds comprising selective IL-2R.alpha. ligands such as
pH-selective IL-2R.alpha. ligands can be used to deliver bioactive
moieties and molecules to cells targeted by the selective
IL-2R.alpha. ligands.
A bioactive moiety or bioactive molecule can itself be selective
for a particular cell population. For example, a bioactive moiety
or bioactive molecule can exhibit a greater or lesser affinity,
potency, and/or activity at the cell being targeted by a selective
or IL-2R.alpha. ligand. For example, the bioactive moiety or
molecule can exhibit greater bioactivity in a low pH tumor
microenvironment when targeted by a pH-selective IL-2R.alpha.
ligand. In this example, the bioactive moiety is directed to cells
located in the low-pH tumor microenvironment that express the
IL-2R.alpha. subunit by the pH-selective IL-2R.alpha. ligand. Thus,
the activity of the pH-selective bioactive moiety is enhanced in
the low-pH tumor microenvironment.
Compounds comprising an IL-2R.alpha. ligand can further comprise a
cytotoxic moiety or molecule. Such compounds can be used to deliver
a cytotoxic compound to a cell expressing the IL-2R.alpha. subunit
such as Tregs. The cytotoxic moiety or molecule can exert
cytotoxicity when bound to the compound or can be cleavable and the
moiety or molecule can be cytotoxic when released from the
compound; or the cytotoxic moiety can be activated by
electromagnetic radiation.
The cytotoxic moiety or molecule can be used to deplete cells
expressing the IL-2R.alpha. ligand being targeted.
IL-2R.alpha. ligand-containing cytotoxic compounds can have more
than one IL-2R.alpha. subunit and thereby can exhibit a higher
affinity and/or selectivity to cells, populations of cells, and
tissue that highly express the IL-2R.alpha. subunit compared to
cells having a lower expression level of the IL-2R.alpha.
subunit.
IL-2R.alpha. ligand-containing cytotoxic compounds can further
include a cell surface targeting component. Such cytotoxic
compounds can exhibit enhanced efficacy to cells, populations of
cells, and tissue expressing both the IL-2R.alpha. subunit and the
surface target component.
Examples of suitable cytotoxic molecules include anti-microtubule
agents, alkylating agents, and DNA minor groove binding agents.
These therapeutic strategies for targeting IL-2R.alpha. expressing
cells with cytotoxic compounds have been demonstrated.
As an example, denileukin diftitox (DAB-IL-2, Ontak) is a
diphtheria-toxin-based fusion protein that depletes CD25-positive
cells including regulatory T cells and has been approved for the
treatment of persistent or recurrent cutaneous T cell lymphoma.
Significant toxicities of the drug include acute hypersensitivity,
vascular leak syndrome and impaired immune function. The latter two
toxicities are due to nonspecific binding of immunotoxin to
macrophages and activated lymphocytes. A modified immunotoxin was
developed to the efficacy and reduce the toxicity. A modified
diphtheria toxin (DT) served as the cytotoxic moiety and IL-2
served as the targeting moiety for targeting cancer cells that
overexpress the IL-2 receptor. T cells, B cells, macrophages and
natural killer cells express the IL-2R.beta. and IL-2R.gamma.c
subunits, whereas the IL-2R.alpha. subunit is uniquely expressed on
cancer cells and activated T cells. Targeting the IL-2R.alpha.
subunit eliminated toxicity.
Cytotoxicity of this recombinant protein was observed to be more
than denileukin diftitox for cells with higher IL-2R.alpha.
expression whereas in cells expressing both IL-2R.alpha. subunit
and the IL-2R.beta. subunit, cytotoxicity varies from cell line to
cell line. The immunotoxin exhibited comparable efficacy to
denileukin diftitox and was more specifically targeted to cells
expressing the IL-2R.alpha. subunit. The fusion protein depletes
IL-2R.alpha.-positive cells including Tregs and has been approved
for the treatment of persistent or recurrent cutaneous T cell
lymphoma.
Another example of an IL-2R.alpha.-targeted cytotoxic compound is
.sup.90Y-daclizumab, an anti-CD25 monoclonal antibody for treating
relapsed Hodgkin's lymphoma. Using the anti-CD25 monoclonal
antibody, daclizumab was directed toward nonmalignant T cells
expressing the IL-2R.alpha. subunit, rather than the tumor cells.
.sup.90Y provided strong .beta. emissions that killed
antigen-non-expressing tumor cells at a distance by a crossfire
effect. Furthermore, the strong Pirradiation killed normal cells in
the tumor microenvironment that nurture the malignant cells in the
lymphomatous mass and thereby provided meaningful treatment of the
Hodgkin's lymphoma.
Compounds comprising an IL-2R.alpha. ligand can further comprise a
moiety having a useful pharmacological activity.
The pharmacological moiety can function synergistically with IL-2R
agonist activity or synergistically with IL-2R antagonist activity,
or the pharmacological moiety may not exhibit synergism with
activity of the IL-2R.alpha. subunit.
Examples of suitable pharmacological moieties include antibodies
and antibody fragments that are inhibitors of checkpoint molecules,
pro-apoptotic and anti-apoptotic molecules, cytotoxic molecules,
agonists of chemokine, antagonists of chemokine, cytokine, growth
factor and other cell surface rectors, and ligands and inhibitors
of cell surface adhesion molecules such as integrins.
Peptides provided by the present disclosure can be synthesized by
methods known in the art, for example, by using standard solid
phase techniques.
A peptide comprising an IL-2R.alpha. ligand provided by the present
disclosure can be modified, for example, by phosphorylation, and by
other methods known in the art. Thus, the peptides provided by the
disclosure can also serve as a basis to prepare peptide mimetics
with similar biological activity.
A variety of techniques are available for constructing peptide
mimetics with the same or similar desired biological activity as a
corresponding peptide but with more favorable activity than the
peptide with respect to solubility, stability, and susceptibility
to hydrolysis and proteolysis.
Pharmaceutical compositions provided by the present disclosure
comprise a compound comprising an IL-2R.alpha. ligand.
Pharmaceutical compositions provided by the present disclosure can
comprise a therapeutically effective amount of a compound
comprising an IL-2R.alpha. ligand or a pharmaceutically acceptable
salt thereof together with a suitable amount of one or more
pharmaceutically acceptable vehicles so as to provide a composition
for administration to a patient. Suitable pharmaceutical vehicles
and methods of preparing pharmaceutical compositions are known.
A pharmaceutical composition can comprise a therapeutically
effective amount of one or more compounds comprising an
IL-2R.alpha. ligand.
A compound comprising an IL-2R.alpha. ligand and/or pharmaceutical
composition thereof can be used in an amount effective to achieve
an intended purpose. For example, for use to treat a disease such
as cancer or an autoimmune disease, a compound comprising an
IL-2R.alpha. ligand and/or pharmaceutical compositions thereof, can
be administered a therapeutically effective amount for treating the
cancer or the autoimmune disease.
The amount of a compound comprising an IL-2R.alpha. ligand and/or
pharmaceutical composition thereof that will be effective in the
treatment of a particular disease can depend on, among other
factors, the patient being treated, the severity of the disease,
the etiology of the disease, the manner of administration and the
judgment of the prescribing physician, and can be determined by
standard clinical techniques known in the art.
A therapeutically effective dose of a compound comprising an
IL-2R.alpha. ligand and/or pharmaceutical composition thereof can
provide a therapeutic benefit without causing substantial toxicity.
Toxicity of a compound comprising an IL-2R.alpha. ligand and/or
pharmaceutical compositions thereof may be determined using
standard pharmaceutical procedures. The dose ratio between toxic
and therapeutic effect is the therapeutic index. A compound
comprising an IL-2R.alpha. ligand and/or pharmaceutical composition
thereof can exhibit a high therapeutic index in treating a disease
such as cancer or an autoimmune disease. A dose of a compound
comprising an IL-2R.alpha. ligand and/or pharmaceutical composition
thereof can be within a range of circulating concentrations that
include an effective dose with minimal toxicity.
A dose of a compound comprising an IL-2R.alpha. ligand provided by
the present disclosure and appropriate dosing intervals may be
selected to maintain a sustained therapeutically effective
concentration of the compound comprising an IL-2R.alpha. ligand
provided by the present disclosure in the blood of a patient, and
in certain embodiments, without exceeding a minimum adverse
concentration.
Pharmaceutical compositions provided by the present disclosure may
further comprise one or more pharmaceutically active compounds in
addition to a compound comprising an IL-2R.alpha. ligand provided
by the present disclosure. Such compounds may be provided, for
example, to treat the disease being treated with a compound
comprising an IL-2R.alpha. ligand or to treat a disease, disorder,
or condition other than the disease being treated with the compound
comprising an IL-2R.alpha. ligand, to treat a side-effect caused by
administering the compound comprising an IL-2R.alpha. ligand, to
augment the efficacy of the a compound comprising an IL-2R.alpha.
ligand, and/or to modulate the activity of the compound comprising
an IL-2R.alpha. ligand.
A compound comprising an IL-2R.alpha. ligand provided by the
present disclosure may be used in combination with at least one
other therapeutic agent. A compound comprising an IL-2R.alpha.
ligand may be administered to a patient together with another
compound for treating the disease. The at least one other
therapeutic agent may be a different compound comprising an
IL-2R.alpha. ligand. A compound comprising an IL-2R.alpha. ligand
and the at least one other therapeutic agent may act additively or
synergistically. The at least one additional therapeutic agent may
be included in the same pharmaceutical composition or vehicle
comprising the compound comprising an IL-2R.alpha. ligand or may be
in a separate pharmaceutical composition or vehicle. Accordingly,
methods provided by the present disclosure further include, in
addition to administering a compound comprising an IL-2R.alpha.
ligand, administering one or more therapeutic agents effective for
treating the disease being treated by the compound comprising an
IL-2R.alpha. ligand or a different disease. Methods provided by the
present disclosure include administration of a compound comprising
an IL-2R.alpha. ligand and one or more other therapeutic agents
provided that the combined administration does not inhibit the
therapeutic efficacy of the compound comprising an IL-2R.alpha.
ligand and/or does not produce adverse combination effects. A
pharmaceutical composition comprising a compound comprising an
IL-2R.alpha. ligand provided by the present disclosure may be
administered with one or more substances, for example, to enhance,
modulate and/or control release, bioavailability, therapeutic
efficacy, therapeutic potency, and/or stability, of the compound
comprising an IL-2R.alpha. ligand. For example, a pharmaceutical
composition comprising a compound comprising an IL-2R.alpha. ligand
can be co-administered with an active agent having pharmacological
effects that enhance the therapeutic efficacy of the compound
comprising an IL-2R.alpha. ligand.
Compounds comprising an IL-2R.alpha. ligand provided by the present
disclosure or a pharmaceutical composition thereof may be included
in a kit that may be used to administer the compound to a patient
for therapeutic purposes. A kit may include a pharmaceutical
composition comprising a compound comprising an IL-2R.alpha. ligand
provided by the present disclosure suitable for administration to a
patient and instructions for administering the pharmaceutical
composition to the patient. The kit can be a kit, for example for
treating cancer or a kit for treating an autoimmune disease. A kit
for use in treating cancer or an autoimmune disease in a patient
can comprise a compound comprising an IL-2R.alpha. ligand provided
by the present disclosure, a pharmaceutically acceptable vehicle
for administering the compound, and instructions for administering
the compound to a patient.
The pharmaceutical compositions can be included in a container,
pack, or dispenser together with instructions for administration.
Instructions supplied with a kit may be printed and/or supplied,
for example, as an electronic-readable medium, a video cassette, an
audiotape, a flash memory device, or may be published on an
internet web site or distributed to a patient and/or health care
provider as an electronic communication.
Compounds comprising an IL-2R.alpha. ligand provided by the present
disclosure may be used for treating cancer in a patient. The cancer
can be, for example, a solid tumor or a metastasis.
A compound comprising an IL-2R.alpha. ligand provided by the
present disclosure or a pharmaceutical composition thereof may be
administered to treat a cancer known to be treated by activation or
inhibition of the IL-2R receptor. Compounds comprising an
IL-2R.alpha. ligand provided by the present disclosure or a
pharmaceutical composition thereof may be administered to treat a
cancer known to be treated by activation or inhibition of the
IL-2R.beta..gamma.c subunits and where simultaneous activation of
the IL-2R.alpha. subunit enhances therapeutic efficacy, modulates
therapeutic efficacy, enhances selective therapeutic efficacy,
and/or minimizes unwanted side effects.
Compounds comprising an IL-2R.alpha. ligand provided by the present
disclosure or a pharmaceutical composition thereof can be used to
treat, for example, one or more of the following cancers: acute
lymphoblastic leukemia, acute myeloid leukemia, adrenocortical
carcinoma, appendix cancer, astrocytoma, atypical teratoid/rhabdoid
tumor, basal cell carcinoma (nonmelanoma), B-cell lymphoma, bladder
cancer, bone cancer, brain and spinal cord tumors, brain stem
cancer, brain tumor, breast cancer, bronchial tumors, Burkitt
lymphoma, carcinoid tumor, carcinoma of head and neck, central
nervous system embryonal tumors, cerebellar astrocytoma, cerebral
astrocytoma/malignant glioma, cervical cancer, chordoma, chronic
lymphocytic leukemia, chronic myelogenous leukemia, colorectal
cancer, craniopharyngioma, cutaneous T-cell lymphoma, desmoplastic
small round cell tumor, ductal carcinoma, dye cancer, endocrine
pancreas tumors (islet cell tumors), endometrial cancer,
ependymoblastoma, esophageal cancer, esthesioneuroblastoma, Ewing
family of tumors, extracranial germ cell tumor, extrahepatic bile
duct cancer, gallbladder cancer, gastric cancer, gastrointestinal
carcinoid tumor, gastrointestinal stromal tumor, gestational
trophoblastic tumor, glioblastoma, glioma, hairy cell leukemia,
head and neck cancer, heart cancer, hematopoetic tumors of the
lymphoid lineage, hepatocellular cancer, Hodgkin lymphoma,
hypopharyngeal cancer, hypothalamic and visual pathway glioma,
IDs-related lymphoma, intraocular melanoma, islet cell tumors,
Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis,
laryngeal cancer, leukemia, lip and oral cavity cancer, male breast
cancer, malignant fibrous histiocytoma, malignant germ cell tumors,
malignant mesothelioma, medulloblastoma, melanoma, Merkel cell
carcinoma, mesothelioma, mouth cancer, multiple endocrine neoplasia
syndrome, multiple myeloma, mycosis fungoides, myelodysplastic,
myeloproliferative neoplasms, nasal cavity and paranasal sinus
cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma,
non-small cell lung cancer, oral cancer, oropharyngeal cancer,
osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian
germ cell tumor, ovarian low malignant potential tumor, pancreatic
cancer, pancreatic neuroendocrine tumors (islet cell tumors),
papillomatosis, paraganglioma, paranasal sinus and nasal cavity
cancer, parathyroid cancer, penile cancer, pharyngeal cancer,
pheochromocytoma, pineal parenchymal tumors, pineoblastoma and
supratentorial primitive neuroectodermal tumors, pituitary tumor,
plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma,
pregnancy and breast cancer, primary central nervous system
lymphoma, primary liver cancer, primary metastatic squamous neck
cancer with occult, prostate cancer, rectal cancer, renal cell
cancer, renal pelvis and ureter, respiratory tract carcinoma,
retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma,
Sezary syndrome, skin cancer, skin cancer, small intestine cancer,
soft tissue sarcoma, squamous cell carcinoma (nonmelanoma), stomach
cancer, supratentorial primitive neuroectodermal tumors, T-cell
lymphoma, testicular cancer, throat cancer, thymoma and thymic
carcinoma, thyroid cancer, transitional cell cancer, urethral
cancer, uterine sarcoma, vaginal cancer, visual pathway and
hypothalamic glioma, vulvar cancer, Waldenstrom macroglobulinemia,
Wilms tumor, and systemic and central metastases of any of the
foregoing.
A compound comprising an IL-2R.alpha. ligand or a pharmaceutical
composition comprising a compound comprising an IL-2R.alpha. ligand
may be administered in conjunction with an agent known or believed
to be effective in treating cancer in a patient, such as the same
cancer being treated with the compound comprising an IL-2R.alpha.
ligand.
A compound comprising an IL-2R.alpha. ligand or a pharmaceutical
composition thereof may be administered in conjunction with a
chemotherapeutic agent, such as, for example, N-acetyl cysteine
(NAC), adriamycin, alemtuzumab, amifostine, arsenic trioxide,
ascorbic acid, bendamustine, bevacizumab, bortezomib, busulfan,
buthionine sulfoxime, carfilzomib, carmustine, clofarabine,
cyclophosphamide, cyclosporine, cytarabine, dasatinib, datinomycin,
defibrotide, dexamethasone, docetaxel, doxorubicin, etoposide,
filgrastim, floxuridine, fludarabine, gemcitabine, interferon
alpha, ipilimumab, lenalidomide, leucovorin, melphalan,
mycofenolate mofetil, paclitaxel, palifermin, panobinostat,
pegfilrastim, prednisolone, prednisone, revlimid, rituximab,
sirolimus, sodium 2-mercaptoethane sulfonate (MESNA), sodium
thiosulfate, tacrolimus, temozolomide, thalidomide, thioguanine,
thiotepa, topotecan, velcade, or a combination of any of the
foregoing.
A compound comprising an IL-2R.alpha. ligand and/or pharmaceutical
composition thereof can be used in combination therapy with other
chemotherapeutic agents including one or more antimetabolites such
as folic acid analogs; pyrimidine analogs such as fluorouracil,
floxuridine, and cytosine arabinoside; purine analogs such as
mercaptopurine, thiogunaine, and pentostatin; natural products such
as vinblastine, vincristine, etoposide, tertiposide, dactinomycin,
daunorubicin, doxurubicin, bleomycin, mithamycin, mitomycin C,
L-asparaginase, and interferon alpha; platinum coordination
complexes such as cis-platinum, and carboplatin; mitoxantrone;
hydroxyurea; procarbazine; hormones and antagonists such as
prednisone, hydroxyprogesterone caproate, medroxyprogesterone
acetate, megestrol acetate, diethylstilbestrol, ethinyl estradiol,
tamoxifen, testosterone propionate, fluoxymesterone, flutamide, and
leuprolide, anti-angiogenesis agents or inhibitors such as
angiostatin, retinoic acids, paclitaxel, estradiol derivatives, and
thiazolopyrimidine derivatives; apoptosis prevention agents;
triptolide; colchicine; luliconazole; and radiation therapy.
A compound comprising an IL-2R.alpha. ligand or a pharmaceutical
composition comprising compound comprising an IL-2R.alpha. ligand
may be administered in conjunction with one or more
chemotherapeutic agents, such as, for example, abarelix,
abiraterone, abiraterone acetate, n-acetyl cysteine, aclarubicin
hydrochloride, adriamycin, adenine, afatinib, afatinib dimaleate,
alemtuzumab, alendronate sodium, alitretinoin, allopurinol sodium,
altretamine, amifostine, aminoglutethimide, aminolevulinic acid,
amrubicin, amsacrine, anastrozole, angiostatin, apremilast,
aprepitant, arsenic trioxide, ascorbic acid, 1-asparaginase,
azacitidine, azathioprine sodium, bazedoxifene (serm), belinostat,
bendamustine hcl, o6-benzylguanine (o6-bg), bevacizumab,
bexarotene, bicalutamide, biricodar, bleomycin sulfate, bortezomib,
bosutinib, brivudine, buserelin, busulfan, buthionine sulfoxime,
cabazitaxel, cabozantinib, capecitabine, carboplatin, carboquone,
carfilzomib, carmofur, carmustine, ceritinib, chlorambucil,
cisplatin, cladribine, clodronate disodium, clofarabine,
crizotinib, cyclophosphamide, cyclosporine, cytarabine, cytosine
arabinoside, dabrafenib, dacarbazine, dactinomycin, dasatinib,
datinomycin, daunorubicin, decitabine, defribrotide, degarelix
acetate, dexamethasone, dexrazoxane hydrochloride, diaziquone,
diethyl stilbestrol, docetaxel, doxifluridine, doxorubicin
hydrochloride, doxorubicin free base, dromostanolone propionate,
dutasteride, eltrombopag, enzalutamide, epirubicin hydrochloride,
eribulin mesylate, erlotinib hydrochloride, estramustine phosphate
sodium, ethinyl estradiol, etoposide phosphate, etoposide,
everolimus, exemestane, fentanyl, filgrastim, fingolimod,
floxuridine, fludarabine phosphate, fluorouracil, fluoxymesterone,
flutamide, formestane, formylmelphalan, fosaprepitant, fotemustine,
fulvestrant, gefitinib, gemcitabine hydrochloride, gemcitabine free
base, glutathione, glyciphosphoramide, glyfosfin, goserelin
acetate, granisetron hydrochloride, heptaplatin, hexyl
5-aminolevulinate, histrelin acetate, hydroxyprogesterone caproate,
hydroxyurea, ibandronate sodium, ibrutinib, icotinib, idarubicin
HCl, idelalisib, idoxuridine, ifosfamide, interferon alpha,
imatinib mesylate, imiquimod, ingenol mebutate, ipilimumab,
irinotecan hydrochloride, ixabepilone, lanreotide acetate,
lapatinib free base, lapatinib ditosylate, lasofoxifene,
lenalidomide, letrozole, leucovorin calcium, leuprolide acetate,
levamisole hydrochloride, levoleucovorin calcium, iobenguane,
lobaplatin, lomustine, maropitant, masoprocol, mechlorethamine
hydrochloride, megestrol acetate, medroxyprogesterone acetate,
melphalan hydrochloride, mercaptopurine, mercaptoethane sulfonate
sodium, methotrexate, methoxsalen, methyl aminolevulinate,
methylene blue, methylisoindigotin, mifamurtide, miltefosine,
miriplatin, mithamycin, mitobronitol, mitomycin C, mitotane,
mitoxantrone hydrochloride, mycophenolate mofetil, nabiximols,
nafarelin, nandrolone, nedaplatin, nelarabine, netupitant,
nilotinib, nilutamide, nimustine, nintedanib, nocodazole,
octreotide, olaparib, omacetaxine mepesuccinate, ondansetron
hydrochloride, oxaliplatin, paclitaxel, palbociclib, palifermin,
palonosetron hydrochloride, pamidronate disodium, panobinostat,
pasireotide, pazopanib hydrochloride, pegfilrastim, pemetrexed
disodium, pentostatin, peplomycin, pipobroman, pirarubicin,
plerixafor, plicamycin, pomalidomide, ponatinib, porfimer sodium,
porfiromycin, pralatrexate, prednimustine, prednisolone,
prednisone, procarbazine hydrochloride, quinagolide hydrochloride,
raloxifene, raltitrexed, radotinib, ranimustine, retinoic acids,
revlimide, rituxinab, romidepsin, ruxolitinib, ruxolitinib
phosphate, semustine, sirolimus, sodium thiosulfate, sorafenib free
base, sorafenib tosylate, streptozocin, sufentanil, sunitinib,
tacrolimus, talaporfin sodium, tamibarotene, tamoxifen citrate,
tapentadol, temoporfin, temozolomide, temsirolimus, teniposide,
teriflunomide, tertiposide, testolactone, testosterone propionate,
thalidomide, thioguanine, thiotepa, thymalfasin, toceranib
phosphate, topotecan hydrochloride, toremifene citrate,
trabectedin, trametinib, tretinoin, trilostane, triptorelin,
tropisetron, uramustine, valrubicin, vandetanib, vedotin,
vemurafenib, verteporfin, vinblastine, vincristine sulfate,
vincristine free base, vindesine, vinorelbine tartrate, vorinostat,
and zoledronic acid.
Compounds provided by the present disclosure can be useful in
treating autoimmune diseases. Autoimmune diseases are defined as
human diseases in which the immune system attacks its own proteins,
cells, and tissues. A comprehensive listing and review of
autoimmune diseases can be found, for example, in The Autoimmune
Diseases (Rose and Mackay, 2014, Academic Press).
Examples of autoimmune diseases include Addison's disease,
agammaglobulinemia, alopecia areata, amyloidosis, ankylosing
spondylitis, anti-GBM/anti-TBN nephritis, antiphospholipid
syndrome, autoimmune angioedema, autoimmune dysautonomia,
autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune
inner ear disease, autoimmune myocarditis, autoimmune pancreatitis,
autoimmune retinopathy, autoimmune urticaria, axonal and neuronal
neuropathy, Balo disease, Bechet's disease, benign mucosal
pemphigoid, bullous pemphigoid, Castleman disease, celiac disease,
Chagas disease, chronic inflammatory demyelinating polyneuropathy,
chronic recurrent multifocal osteomyelitis, Churg-Strauss,
cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease,
congenital heart block, Coxsackie myocarditts, CREST syndrome,
Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's
disease, discoid lupus, Dressler's syndrome, endometriosis,
eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum,
essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia,
fibrosing alveolitis, giant cell arteritis, giant cell myocarditis,
glomerulonephritis, Goodpasture's syndrome, granulomatosis with
polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto
thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpes
gestationis or pemphigoid gestationis, hypogammaglobulinemia, IgA
nephropathy, IgG4-related sclerosing disease, immune
thrombocytopenic purpura, inclusion body myositis, interstitial
cystitis, juvenile arthritis, juvenile diabetes, juvenile myositis,
Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic
vasculitis, lichen planus, lichen sclerosis, ligneous
conjunctivitis, linear IgA disease, lupus, Lyme disease chronic,
Meniere's diseases, microscopic polyangiitis, mixed connective
tissue disease, Mooren's ulcer, Mucha-Habermann disease, multiple
sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis,
optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis,
palindromic rheumatism, PANDAS, paraneoplastic cerebellar
degeneration, paroxysmal nocturnal hemoglobinuria, Parry Romberg
syndrome, pars planitis, Parsonage-Turner syndrome, pemphigus,
peripheral neuropathy, perivenous encephalomyelitis, pernicious
anemia, POEMS syndrome, polyarteritis nodosa, polyglandular
syndromes, polymyalgia rheumatica, polymyositis, postmyocardial
infarction syndrome, postpericardiotomy syndrome, primary biliary
cirrhosis, primary sclerosing cholangitis, progesterone dermatitis,
psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma
gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex
sympathetic dystrophy, relapsing polychondritis, restless legs
syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid
arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma,
Sjogren's syndrome, sperm and testicular autoimmunity, stiff person
syndrome, subacute bacterial endocarditis, Susac's syndrome,
sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis,
thrombocytopenic purpura, Tolosa-Hunt syndrome, transverse
myelitis, Type 1 diabetes, ulcerative colitis, undifferentiated
connective tissue disease, uveitis, vasculitis, vitiligo, and
Wegener's granulomatosis.
A compound comprising an IL-2R.alpha. ligand or a pharmaceutical
composition comprising a compound comprising an IL-2R.alpha. ligand
may be administered in conjunction with an agent known or believed
to be effective in treating an autoimmune disease in a patient.
A compound comprising an IL-2R.alpha. ligand or a pharmaceutical
composition comprising a compound comprising an IL-2R.alpha. ligand
may be administered in conjunction with an IL-15 agonist for
treating an autoimmune disease. For example, a suitable IL-15
agonist is disclosed in PCT International Publication No. WO
2017/062832 A1 and in PCT International Publication No. WO
2015/153753 A1.
Compounds comprising an IL-2R.alpha. ligand provided by the present
disclosure and pharmaceutical compositions thereof may be
administered to a patient to treat a disease associated with the
activation, proliferation, metabolism, and/or differentiation of
T-cells.
Compounds comprising an IL-2R.alpha. ligand provided by the present
disclosure and pharmaceutical compositions thereof may be
administered to a patient to treat an organ transplant.
Compounds comprising an IL-2R.alpha. ligand provided by the present
disclosure and pharmaceutical compositions thereof may be
administered to treat an inflammatory disease.
A compound comprising an IL-2R.alpha. ligand or a pharmaceutical
composition comprising a compound comprising an IL-2R.alpha. ligand
may be administered in conjunction with an agent known or believed
to interfere with cell proliferation.
A compound comprising an IL-2R.alpha. ligand or a pharmaceutical
composition comprising a compound comprising an IL-2R.alpha. ligand
may be administered in conjunction with an agent known or believed
to interfere with metabolism. A compound comprising an IL-2R.alpha.
ligand or a pharmaceutical composition comprising a compound
comprising an IL-2R.alpha. ligand may be administered in
conjunction with an agent known or believed to interfere with
mitochondrial metabolism. A compound comprising an IL-2R.alpha.
ligand or a pharmaceutical composition comprising a compound
comprising an IL-2R.alpha. ligand may be administered in
conjunction with an agent known or believed to be an
anti-metabolite. A compound comprising an IL-2R.alpha. ligand or a
pharmaceutical composition comprising a compound comprising an
IL-2R.alpha. ligand may be administered in conjunction with an
agent known or believed to interfere RNA transcription. A compound
comprising an IL-2R.alpha. ligand or a pharmaceutical composition
comprising a compound comprising an IL-2R.alpha. ligand may be
administered in conjunction with an agent known or believed to
interfere with RNA translation. A compound comprising an
IL-2R.alpha. ligand or a pharmaceutical composition comprising a
compound comprising an IL-2R.alpha. ligand may be administered in
conjunction with an agent known or believed to interfere with
protein synthesis. A compound comprising an IL-2R.alpha. ligand or
a pharmaceutical composition comprising a compound comprising an
IL-2R.alpha. ligand may be administered in conjunction with an
agent known or believed to interfere with synthesis of precursors
for DNA synthesis and replication. A compound comprising an
IL-2R.alpha. ligand or a pharmaceutical composition comprising a
compound comprising an IL-2R.alpha. ligand may be administered in
conjunction with an agent known or believed to interfere with
purine synthesis. A compound comprising an IL-2R.alpha. ligand or a
pharmaceutical composition comprising a compound comprising an
IL-2R.alpha. ligand may be administered in conjunction with an
agent known or believed to interfere with nucleoside synthesis. A
compound comprising an IL-2R.alpha. ligand or a pharmaceutical
composition comprising a compound comprising an IL-2R.alpha. ligand
may be administered in conjunction with an agent known or believed
to interact with mTOR. A compound comprising an IL-2R.alpha. ligand
or a pharmaceutical composition comprising a compound comprising an
IL-2R.alpha. ligand may be administered in conjunction with an
agent known or believed to interact be an mTOR inhibitor. A
compound comprising an IL-2R.alpha. ligand or a pharmaceutical
composition comprising compound comprising an IL-2R.alpha. ligand
may be administered in conjunction with an agent known or believed
to interfere with cell cycle checkpoints.
A compound comprising an IL-2R.alpha. ligand or a pharmaceutical
composition comprising a compound comprising an IL-2R.alpha. ligand
may be administered in conjunction with a checkpoint inhibitor
including CTLA-4 inhibitors such as ipilimumab, PD1 inhibitors such
as pembrolizumab and cemiplimab, and PD-LI inhibitors such as
atezolizumab, avelumab, and durvalumab. A compound comprising an
IL-2R.alpha. ligand or a pharmaceutical composition comprising a
compound comprising an IL-2R.alpha. ligand may be administered in
conjunction with an immunomodulator such as CD137/4-1BB, CD27,
GIYR, and/or OC40.
A compound comprising an IL-2R.alpha. ligand or a pharmaceutical
composition comprising a compound comprising an IL-2R.alpha. ligand
may be administered in conjunction with an agent known or believed
to be cytotoxic. A compound comprising an IL-2R.alpha. ligand or a
pharmaceutical composition comprising a compound comprising an
IL-2R.alpha. ligand may be administered in conjunction with an
agent known or believed to be cytostatic. A compound comprising an
IL-2R.alpha. ligand or a pharmaceutical composition comprising a
compound comprising an IL-2R.alpha. ligand may be administered in
conjunction with an agent known or believed to cause DNA damage. A
compound comprising an IL-2R.alpha. ligand or a pharmaceutical
composition comprising a compound comprising an IL-2R.alpha. ligand
may be administered in conjunction with an agent known or believed
to cause cell cycle arrest. A compound comprising an IL-2R.alpha.
ligand or a pharmaceutical composition comprising a compound
comprising an IL-2R.alpha. ligand may be administered in
conjunction with an agent known or believed to cause mitotic
catastrophe.
A compound comprising an IL-2R.alpha. ligand or a pharmaceutical
composition comprising a compound comprising an IL-2R.alpha. ligand
may be administered in conjunction with an agent known or believed
to modulate drug resistance. A compound comprising an IL-2R.alpha.
ligand or a pharmaceutical composition comprising a compound
comprising an IL-2R.alpha. ligand may be administered in
conjunction with an agent known or believed to reduce multi-drug
resistance. A compound comprising an IL-2R.alpha. ligand or a
pharmaceutical composition comprising a compound comprising an
IL-2R.alpha. ligand may be administered in conjunction with an
agent known or believed to interact with membrane proteins. A
compound comprising an IL-2R.alpha. ligand or a pharmaceutical
composition comprising a compound comprising an IL-2R.alpha. ligand
may be administered in conjunction with an agent known or believed
to interact with plasma membrane proteins. A compound comprising an
IL-2R.alpha. ligand or a pharmaceutical composition comprising a
compound comprising an IL-2R.alpha. ligand may be administered in
conjunction with an agent known or believed to interact with
nuclear membrane proteins. A compound comprising an IL-2R.alpha.
ligand or a pharmaceutical composition comprising a compound
comprising an IL-2R.alpha. ligand may be administered in
conjunction with an agent known or believed to interact with major
vault protein or proteins. A compound comprising an IL-2R.alpha.
ligand or a pharmaceutical composition comprising a compound
comprising an IL-2R.alpha. ligand may be administered in
conjunction with an agent known or believed to interact with gen
products of the MVP (major vault protein) gene.
A compound comprising an IL-2R.alpha. ligand or a pharmaceutical
composition comprising a compound comprising an IL-2R.alpha. ligand
may be administered in conjunction with an agent known or believed
to modulate glutathione concentration. A compound comprising an
IL-2R.alpha. ligand or a pharmaceutical composition comprising a
compound comprising an IL-2R.alpha. ligand may be administered in
conjunction with an agent known or believed to modulate glutathione
concentration within cells. A compound comprising an IL-2R.alpha.
ligand or a pharmaceutical composition comprising a compound
comprising an IL-2R.alpha. ligand may be administered in
conjunction with an agent known or believed to decrease glutathione
concentration within cells. A compound comprising an IL-2R.alpha.
ligand or a pharmaceutical composition comprising a compound
comprising an IL-2R.alpha. ligand may be administered in
conjunction with an agent known or believed to reduce glutathione
uptake into cells. A compound comprising an IL-2R.alpha. ligand or
a pharmaceutical composition comprising a compound comprising an
IL-2R.alpha. ligand may be administered in conjunction with an
agent known or believed to reduce glutathione synthesis. A compound
comprising an IL-2R.alpha. ligand or a pharmaceutical composition
comprising a compound comprising an IL-2R.alpha. ligand may be
administered in conjunction with an agent known or believed to
reduce glutathione synthesis within cells.
A compound comprising an IL-2R.alpha. ligand or a pharmaceutical
composition comprising a compound comprising an IL-2R.alpha. ligand
may be administered in conjunction with an agent known or believed
to interfere with neovascularization. A compound comprising an
IL-2R.alpha. ligand or a pharmaceutical composition comprising a
compound comprising an IL-2R.alpha. ligand may be administered in
conjunction with an agent known or believed to reduce
neovascularization. A compound comprising an IL-2R.alpha. ligand or
a pharmaceutical composition comprising a compound comprising an
IL-2R.alpha. ligand may be administered in conjunction with an
agent known or believed to promote neovascularization.
A compound comprising an IL-2R.alpha. ligand or a pharmaceutical
composition comprising a compound comprising an IL-2R.alpha. ligand
may be administered in conjunction with an agent known or believed
to interfere with hormone homeostasis. A compound comprising an
IL-2R.alpha. ligand or a pharmaceutical composition comprising a
compound comprising an IL-2R.alpha. ligand may be administered in
conjunction with an agent known or believed to interfere with
hormone synthesis. A compound comprising an IL-2R.alpha. ligand or
a pharmaceutical composition comprising a compound comprising an
IL-2R.alpha. ligand may be administered in conjunction with an
agent known or believed to interfere with hormone receptor binding.
A compound comprising an IL-2R.alpha. ligand or a pharmaceutical
composition comprising a compound comprising an IL-2R.alpha. ligand
may be administered in conjunction with an agent known or believed
to interfere with hormone signal transduction.
A compound comprising an IL-2R.alpha. ligand or a pharmaceutical
composition comprising a compound comprising an IL-2R.alpha. ligand
may be administered in conjunction with an agent known or believed
to interfere with growth factor homeostasis. A compound comprising
an IL-2R.alpha. ligand or a pharmaceutical composition comprising a
compound comprising an IL-2R.alpha. ligand may be administered in
conjunction with an agent known or believed to interfere with
growth factor synthesis. A compound comprising an IL-2R.alpha.
ligand or a pharmaceutical composition comprising a compound
comprising an IL-2R.alpha. ligand may be administered in
conjunction with an agent known or believed to interfere with
growth factor receptor expression. A compound comprising an
IL-2R.alpha. ligand or a pharmaceutical composition comprising a
compound comprising an IL-2R.alpha. ligand may be administered in
conjunction with an agent known or believed to interfere with
growth factor binding to growth factor receptors. A compound
comprising an IL-2R.alpha. ligand or a pharmaceutical composition
comprising a compound comprising an IL-2R.alpha. ligand may be
administered in conjunction with an agent known or believed to
interfere with growth factors binding to growth factor receptors. A
compound comprising an IL-2R.alpha. ligand or a pharmaceutical
composition comprising a compound comprising an IL-2R.alpha. ligand
may be administered in conjunction with an agent known or believed
to interfere with growth factor receptor signal transduction. A
compound comprising an IL-2R.alpha. ligand or a pharmaceutical
composition comprising a compound comprising an IL-2R.alpha. ligand
may be administered in conjunction with an agent known or believed
to interfere with the Hedgehog (Hh) signaling. A compound
comprising an IL-2R.alpha. ligand or a pharmaceutical composition
comprising a compound comprising an IL-2R.alpha. ligand can be
administered in conjunction with an agent known or believed to
inhibit the Hedgehog pathway signaling. A compound comprising an
IL-2R.alpha. ligand or a pharmaceutical composition comprising a
compound comprising an IL-2R.alpha. ligand may be administered in
conjunction with an agent known or believed to inhibit ALK
(anaplastic lymphoma kinase) pathway signaling. A compound
comprising an IL-2R.alpha. ligand or a pharmaceutical composition
comprising a compound comprising an IL-2R.alpha. ligand may be
administered in conjunction with an agent known or believed to
inhibit non-homologous end joining (NHEJ) is a pathway.
A compound comprising an IL-2R.alpha. ligand or a pharmaceutical
composition comprising a compound comprising an IL-2R.alpha. ligand
may be administered in conjunction with one or more agents known or
believed to be a VEGFR (vascular endothelial growth factor
receptor) inhibitor, a RTK (receptor tyrosine kinase) inhibitor, a
sodium channel current blocker, aFAK (focal adhesion kinase)
inhibitor, a GLI (glioma-associated oncogene) inhibitor, a GLI1
inhibitor, a GLI2 inhibitor, a GLI3 inhibitor, a MAPK
(mitogen-activated protein kinase) inhibitor, a MAPK/ERK pathway
(also known as Ras-Raf-MEK-ERK pathways) inhibitor, a MEK1
inhibitor, a MEK2 inhibitor, a MEK5 inhibitor, a MEK5/ERK5
inhibitor, aRTA (renal tubular acidosis) inhibitor, a ALK
(anaplastic lymphoma kinase) inhibitor, Aa LK kinase inhibitor, a
nuclear translocation inhibitor, a PORCN (porcupine) inhibitor, a
5-ARI (5.alpha.-reductase inhibitor), topoisomerase inhibitor, a
Ras (rat sarcoma) inhibitor, a K-ras inhibitor, a CERK (ceramide
kinase) inhibitor, a PKB (protein kinase B, also known as AKT)
inhibitor, a AKT1 inhibitor, EZH2 (enhacer of zeste homolog 2)
inhibitor, a BET (bromodomain and extraterminal domain motif)
inhibitor, a SYK (apleen tyrosine kinase) inhibitor, JAK (janus
kinase) inhibitors, a SYK/JAK inhibitor, a IDO (indoleamine-pyrrole
2,3-dioxygenase) inhibitor, a IDO1 inhibitor, a RXR (retinoic X
receptors) activating agent, a selectively RXR activating agent, a
p-glycoprotein inhibitor, a ERK inhibitor, a PI3K
(phosphatidylinositol-4,5-bisphosphate 3-kinase) inhibitor, a BRD
(bromodomain-containing protein) inhibitor, a BRD2 inhibitor, a
BRD3 inhibitor, a BRD4 inhibitor, a BRDT (bromodomain
testis-specific protein) inhibitor, a reverse transcriptase
inhibitor, a NRT (nucleoside analog reverse-transcriptase)
inhibitor, a PIM (proviral integrations of moloney virus)
inhibitor, a EGFR (epidermal growth factor receptor) inhibitor, a
photosensitizer, a radiosensitizer, a ROS (proto-oncogene, receptor
tyrosine kinase) inhibitor, a ROS1 (proto-oncogene 1) inhibitor, a
CK (caseine kinase) inhibitor, a CK2 inhibitor, a Bcr-Abl
(breakpoint cluster region--Abelson proto-oncogene) tyrosine-kinase
inhibitor such as dasatinib, a microtubule stabilizing agent, a
microtubule depolymerisation/disassembly inhibitor, a DNA
intercalator, an androgen receptor antagonist, a chemoprotective
agents, a HDAC (histone deacetylase) inhibitor, a DPP (dipeptidyl
pepdidase) inhibitor, a DPP-4 inhibitor, BTK (Bruton's tyrosine
kinase) inhibitor, a kinase inhibitor such as imatinib, a tyrosine
kinase inhibitor such as nilotinib, a ARP (poly (ADP-ribose)
polymerase) inhibitor, a CDK (cyclin-dependent kinase) inhibitor, a
CDK4 inhibitor, a CDK6 inhibitor, a CDK4/6 inhibitor, a HIF1.alpha.
(hypoxia-inducible factor 1-.alpha.) inhibitor, a DNA ligase
inhibitor, a DNA ligase IV inhibitor, a NHEJ (non-homologous end
joining) inhibitor, a DNA ligase IV, a NHEJ inhibitor and a RAF
inhibitor, a TKI and a RAF inhibitor, a TKI and RAF inhibitor such
as sorafenib, a PDT (photodynamic therapy) sensitizer, an ATR
(ataxia telangiectasia- and Rad3-related protein kinase) inhibitor,
or a combination of any of the foregoing.
A compound comprising an IL-2R.alpha. ligand or a pharmaceutical
composition comprising a IL-2R.alpha. ligand may be administered in
conjunction with one or more chemotherapeutic agents, such as, for
example, a VEGFR inhibitor such as fruquintinib, motesanib/AMG-706,
vatalanib; a RTK inhibitor such as ponatinib; a sodium channel
blocker such as GS967; a FAK inhibitor such as TAE226; a GLI1 and
GLI2 inhibitor such as GANT61, a MEK inhibitor such as binimetinib;
a RTA inhibitor such as linifanib; an ALK inhibitor such as
brigstinib; bromopyruvic acid; a DNA alkylating agent such as
thiotepa; nuclear translocations factors such as JSH-23; a PORCn
inhibitor such as Wnt-C59; a 5.alpha.-reductase inhibitor such as
dutasteride; a topoisomerase inhibitor such as carubicin; a RAS
inhibitor such as Kobe0065; a CerK inhibitor such as NVP-231; an
AKT inhibitor such as uprosertib; a EZH2 inhibitor such as GSK-503;
a BET bromodomain inhibitor such as OTX015; a MEK5/ERK5 inhibitor
such as BIX02189; a Syl/JAK inhibitor such as cerdulatinib; an IDO1
inhibitor such as NLG919; a retinoic X receptor activating agent
such as bexsrotene; a PGP inhibitor such as acotiamide or
actotiamide HCl; an Erk inhibitor such SCH772984; a PI3K inhibitor
such as gedatolisib; a JAK inhibitor such as ruxolitinib; an AKT
inhibitor such as afuresertib or afuresertib HCl; an ALK1 inhibitor
such as ceritinib; an HDAC inhibitor such as abexinostat; a DPP
inhibitor such as oamarigliptin; an EGFR inhibitor such as
gefittinib; an EZH2 inhibitor such as GSK126; a BTK inhibitor such
as ibrutinib; a kinase inhibitor such as imatinin HCl; an IDO
inhibitor such as INCB024360; a DNA crosslinker such as mitomycin
C; a tyrosine kinase inhibitor such as nilotinib, a PARP inhibitor
such as olaparib; a tubulin stabilization promoter such as
paclitaxel; a CDK4/6 inhibitor such as palbociclib; a RTK inhibitor
such as sunitinib; a PDT sensitizer such as tslsporfin; a
p-glycoprotein inhibitor such as tariquidar; an ATR inhibitor such
as VE-822; an HDAC inhibitor such as PCI-24781; a DPP inhibitor
such as omarigliptin; an EGFR inhibitor such as gefinib; an EZH2
inhibitor such as GSK126; a BTK inhibitor such as irbrutinib; an
IDO inhibitor such as INCB024360; or a combination of any of the
foregoing.
An IL-2R.alpha. binding compound provided by the present disclosure
can be used as a vaccine adjuvant.
IL-2R.alpha. binding compounds provided by the present disclosure
can be useful when combined with certain vaccines, including cancer
neo-antigen vaccines. Mutations in tumor DNA produce new protein
sequences that are foreign to the body. Vaccines can be designed to
specifically activate a patient's immune system with respect to
tumor-specific neoantigens. When administered in combination with a
neo-antigen vaccine, IL-2R.alpha. binding compounds provided by the
present disclosure can expand and proliferate neo-antigen-specific
T-cells in the tumor microenvironment and thereby drive maximal
expansion of vaccine-induced neoantigen-specific T-cells for the
treatment of cancer.
IL-2R.alpha. ligands and IL-2R.alpha. constructs provided by the
present disclosure can be used as adjuvants. An adjuvant refers to
a compound that enhances the efficacy of a vaccine without directly
participating in the protective immunity. For example, an
IL-2R.alpha. binding compound provided by the present disclosure
can be used in conjunction with a cancer vaccine.
IL-2R.alpha. ligands and IL-2R.alpha. ligand constructs provided by
the present disclosure can be useful for cell therapy when
engineered to be expressed on the membrane surface of cells that
also express the IL-2R.alpha. subunit. Adoptive immunotherapy using
NK cells or using re-targeted chimeric antigen receptor (CAR)
T-cells is currently being studied as a treatment for neoplasms and
viral infections. One challenge with these cell therapies is the
suboptimal sustained survival of the infused cells.
DNA encoding an IL-2R.alpha. binding compound fused to a membrane
protein in such away that the IL-2R.alpha. binding compound is
expressed on the extracellular surface of a cell can be constructed
using standard techniques. When the fusion protein comprising the
IL-2R.alpha. binding compound is expressed, IL-7 receptors on the
cell can become activated leading to long-term persistence of the
cell.
DNA encoding an IL-2R.alpha. binding compound can be incorporated
into a cell and can be configured to produce an IL-2R.alpha.
binding compound provided by the present disclosure. The
IL-2R.alpha. binding compound can be secreted from the cell and can
interact with the secreting cells (i.e., autocrine signaling)
and/or cells in the vicinity of the secreting cell (i.e., paracrine
signaling). A secreted IL-2R.alpha. binding compound provided by
the present disclosure can be an IL-2R agonist and can be designed
to localize near the secreting cell.
An IL-2R.alpha. binding compound provided by the present disclosure
can be used to expand non-regulatory T-cells within a patient or
within a biological sample. Methods of increasing the ratio of
non-regulatory T-cells to Treg cells can comprise contacting a
population of T-cells with an effective amount of an IL-2R.alpha.
binding compound. The ratio can be measured by determining the
ratio of CD3+FOXP3+ cells to CD3+FOXP3-cells within the population
of T-cells. A typical Treg frequency in human blood is 5% to 10% of
the total CD4+CD3.sup.+ T-cells, however, in certain diseases this
percentage may be lower or higher.
An IL-2R.alpha. binding compound can be used to expand NK cells. NK
cells modified with chimeric antigen receptors (CARs), which
redirect immune cell activity to target cancer cells have been
demonstrated to exhibit improved antitumor responses. CARs can
comprise an antibody-derived extracellular domain, which binds to
the desired tumor-associated antigen (TAA) and triggers an
intracellular signaling cascade to activate the immune cell against
the target cells.
NK cells can be genetically engineered for enhanced expression of
one or more tumor targeting receptors such as NKG2D with
membrane-bound IL-2R.alpha. binding compound, which can prolong the
persistence and potency of the NK cells.
CAR T-cells can be genetically engineered to co-express a tethered
form of an IL-2R.alpha. binding compound provided by the present
disclosure to support in vivo persistence and maintenance of an
immature state of differentiation and to exhibit in vivo antitumor
activity.
IL-2R.alpha. binding compounds provided by the present disclosure
can also be utilized as commercial reagents for various medical
research and diagnostic uses. Such uses include, for example, (1)
use as a calibration standard for quantitating the activities of
candidate IL-2R agonists in a variety of functional assays; (2) use
to maintain the proliferation and growth of IL-7-dependent cell
lines; (3) use in structural analysis of IL-2R through
co-crystallization; (4) use to investigate the mechanism of IL-2R
signal transduction/receptor activation; and (5) other research and
diagnostic applications where IL-2R is activated or such activation
is conveniently calibrated against a known quantity of an IL-2R
agonist.
Aspects of the present invention include nucleic acids encoding for
an IL-2R.alpha. binding compound provided by the present
disclosure.
A nucleic acid or isolated polynucleotide encoding an IL-2R.alpha.
provided by the present disclosure can be incorporated into
expression vectors depending in part on the host cells used to
produce the IL-2R.alpha. binding compound. Generally, the nucleic
acids can be operably linked to any number of regulatory elements
such as, for example, promoters, origin of replication, selectable
markers, ribosomal binding sites, and/or inducers. The expression
vectors can be extra-chromosomal or integrating vectors.
The nucleic acids and/or expression can be transformed into any
number of different types of host cells including mammalian,
bacterial, yeast, insect and/or fungal cells, with mammalian cells
such as CHO cells.
A nucleic acid encoding an IL-2R.alpha. binding compound can
comprise a first nucleic acid sequence encoding an IL-2R.alpha.
ligand; a second nucleic acid sequence encoding a peptidyl ligand
linker; and a third nucleic acid sequence encoding an IL-2R.alpha.
ligand, an Rye ligand, and/or a construct partner.
A nucleic acid encoding an IL-2R.alpha. ligand fusion protein can
comprise a first nucleic acid sequence encoding the IL-2R.alpha.
ligand provided by the present disclosure; and a second nucleic
acid sequence encoding a fusion partner. A nucleic acid encoding an
IL-2R.alpha. ligand fusion protein can comprise a nucleic acid
encoding an IL-2R.alpha. ligand and the fusion partner. A nucleic
acid encoding an IL-2R.alpha. ligand fusion protein can further
comprise a nucleic acid segment encoding a construct linker and a
nucleic acid encoding an IL-2R.alpha. ligand fusion protein can
comprise a nucleic acid encoding an IL-2R.alpha. ligand, the fusion
partner, and the construct linker.
The fusion partner can comprise, for example, HSA, an Fc-fragment,
an IgG, an antibody directed to a cell-specific antigen, and an
antibody directed to a cell-specific receptor.
A nucleic acid encoding an IL-2R.alpha. fusion protein can further
comprise a nucleic acid encoding a peptidyl linker, where the
peptidyl linker is configured to bind the IL-2R.alpha. ligand to
the fusion partner.
A nucleic acid provided by the present disclosure can encode a
fusion protein comprising an IL-2R.alpha. ligand, and a linker
binding the C-terminus of the IL-2R.alpha. ligand to HSA.
A nucleic acid provided by the present disclosure can encode a
fusion protein comprising a dimeric Fc-Fragment of IgG1, IgG2, or
IgG4, an IL-2R.alpha. ligand, and a linker binding the N-terminus
of an IL-2R.alpha. ligand to the C-terminus of one CH3 domain of
the dimeric Fc-fragment.
A nucleic acid provided by the present disclosure can encode a
fusion protein comprising a dimeric Fc-Fragment of IgG1, IgG2, or
IgG4, two IL-2R.alpha. ligands, and a linker binding the N-terminus
of each of the two IL-2R.alpha. ligands to the C-terminus of each
CH3 domain of the dimeric Fc-fragment.
A nucleic acid provided by the present disclosure can encode a
fusion protein comprising a heavy chain of an immunoglobulin
molecule such as IgG1, IgG2, or IgG4, an IL-2R.alpha. ligand, and a
Fc linker bonding the N-terminus of the IL-2R.alpha. ligand to the
C-terminus of the Fc region.
A nucleic acid provided by the present disclosure can encode for an
IL-2R.alpha. ligand comprising an amino acid sequence of any one of
SEQ ID NOS: 1-307 and 400-423, or can encode for an amino acid
sequence comprising an amino acid sequence having greater than 60%,
greater than 70%, greater than 80%, greater than 85%, greater than
90%, or greater than 95% sequence similarity to any one of SEQ ID
NOS: 1-307 and 400-423.
A nucleic acid provided by the present disclosure can encode for a
homomeric IL-2R.alpha. ligand comprising two or more IL-2R.alpha.
ligands provided by the present disclosure.
Aspects of the invention further include a host cell comprising an
expression vector comprising a nucleic acid encoding an
IL-2R.alpha. ligand or an IL-2R.alpha. binding compound provided by
the present disclosure.
Methods provided by the present disclosure include methods of
making an IL-2R.alpha. ligand or an IL-2R.alpha. binding compound
provided by the present disclosure, comprising culturing a host
cell, wherein the host cell comprises an expression vector
comprising a nucleic acid encoding an IL-2R.alpha. ligand or an
IL-2R.alpha. binding compound provided by the present disclosure,
under conditions where the IL-2R.alpha. ligand or the IL-2R.alpha.
binding compound is expressed, and recovering the expressed
IL-2R.alpha. ligand or IL-2R.alpha. binding compound.
EXAMPLES
The following examples describe in detail methods used for
determining the activity of peptides comprising the IL-2R.alpha.
subunit. It will be apparent to those skilled in the art that many
modifications, both to materials and methods, may be practiced
without departing from the scope of the disclosure.
Example 1
Phage Display pIII Library Panning Against Fc-Fusions on Magnetic
Beads (Acid Elution) Library Panning Procedure
Fifty (50) .mu.L of Protein G Dynabeads.RTM. (Invitrogen) was used
for each library sample. After resuspending the stock bottle, the
desired volume of beads was transferred to a sterile microfuge tube
and applied to the magnet.
With the beads on a magnet, the supernatant was removed, and the
beads were washed with 1 mL of PT buffer (1.times.PBS, 0.05%
Tween.RTM.-20).
The supernatant was removed and 1 mL of PBS+1% BSA+0.05%
Tween.RTM.-20 was added and mixed at 25.degree. C. for at least 1
hour to block the beads.
A tube was applied to the magnet and the blocking solution was
removed. For each library to be tested, 5 .mu.g of a Fc-fused
receptor of interest was added to each library sample for each
round to bring the total volume to at least 400 .mu.L. The samples
were mixed at 25.degree. C. for at least 1 h. The sample was
applied to the magnet and the supernatant was removed.
Two-hundred 200 .mu.L of PT buffer was added for each 50 .mu.L of
bead. The sample was thoroughly mixed and 200 .mu.L aliquots were
transferred into tubes that were pre-labeled for each library to be
screened. An additional 500 .mu.L of PT was added to each tube, the
samples mixed, and then applied to the magnet. A total of 700
.mu.L/tube was used for the wash.
The wash was removed and 500 .mu.L of 250 nM Fc blocking peptide
diluted in PBT (PBS+0.5% BSA+0.05% Tween.RTM.-20) was added to each
sample. The stock concentration was 25 .mu.M (100.times.). The
samples were incubated at 4.degree. C. for at least 30 min while
rotating. Following the incubation, the samples were applied to the
magnet and the blocking peptide solution was removed prior to
adding the libraries. One (1) mL aliquots of the libraries removed
from the -20.degree. C. freezer. One-hundred (100 .mu.L of
10.times.BT buffer (5% BSA, 0.5% Tween.RTM.-20 in 1.times.PBS) was
added to each tube and vortexed. Eleven (11) .mu.L of Fc blocking
peptide was added to each library sample and vortexed. The library
samples were transferred to pre-labeled tubes containing beads. The
samples were then incubated at 4.degree. C. on the rotator for at
least 2 h. For the additional rounds of screening, 1 mL aliquots of
the amplification from the previous round from each library was
used. Fc blocking peptide was then added at the concentration
indicated in step 6 (10 .mu.L blocking peptide).
The beads were recovered with the magnet and the phage solution
removed. The beads were washed 2.times. with 1 mL of PT buffer.
Five-hundred (500) .mu.L of PT buffer was added and the suspension
was transferred to a clean tube. The beads were recovered on the
magnet and the final wash removed.
Four-hundred seventy-five (475) .mu.L of phage elution buffer was
added to each well (0.2 M glycine-HCL, pH 2.2, 1 mg/mL BSA). The
samples were incubated at 25.degree. C. for 10 min on the rotator.
The beads were recovered on the magnet and the eluted phage
transferred to a clean tube.
Twenty-five (25) .mu.L of neutralization buffer (2M Tris Base) was
added to the 475 .mu.L of elution. The neutralized samples were
maintained at 4.degree. C. until the TG1 cells were ready
amplification. The samples were stored at -20.degree. C. after
screening. Fifty (50) L (about 10% of the total volume) was
transferred to a 1.5 mL microfuge tube and store at -20.degree. C.
for use in deep sequencing.
Example 2
TG1 Culture and Library Amplification
Afresh T G1 (or OmniMax) culture was grown for about 1 to 1.5 h
after adding the libraries to the beads. 2X-YT medium (10 mL) was
placed into a 50 mL Falcon.RTM. tube. Two-hundred (200) .mu.L of
the TG1 overnight was added to the falcon tube. 2X-YT medium (600
.mu.L) was placed in a cuvette for OD600 blank. The culture was
grown at 250 rpm and 37.degree. C., taking the first OD measurement
after 60 min. The TG1 cells should be in log phase at the time of
use with an OD600 of 0.5-0.7.
Eluted phage (400 .mu.L to 450 .mu.L) was added to 1 mL of the TG1
cells at an OD600 of 0.5-0.7 in a 50 mL Falcon.RTM. tube. The phage
and TG1 cells were incubated at 37.degree. C. for 30 min without
shaking. About 50 .mu.L to 100 .mu.L was set aside for titering and
characterization.
2YT medium (10.5 mL) was added to 12 .mu.L of carbenicillin (carb)
(100 mg/mL to make 100 .mu.g/mL) and 24 .mu.L of 50% glucose (to
make 0.1% glucose) and the cells incubated while shaking at
37.degree. C. at 250 rpm for 1 h.
M13K07 helper phage (5.times.10.sup.10 pfu, 24 .mu.L of the stock,
2.times.10.sup.2 pfu/mL) was then added and swirled to mix. The
phage and cells were incubated at 37.degree. C. for 30 min without
shaking.
Kanamycin was diluted to 3 mg/mL and arabinose to 2.4% in 2YT
medium/Carbenicillin-100/0.1% glucose and 100 .mu.L was added to
each amplification. The mixture was incubated overnight at
37.degree. C. and 250 rpm.
The culture was transferred to a 50 mL high-speed VWR centrifuge
tube and centrifuged at 8,000 g for 15 min at 4.degree. C. in a
JSP-F50C centrifuge to pellet the cells.
The supernatant was transferred to a 50 mL high-speed VWR
centrifuge tube and 0.2 volumes of PEG/NaCl (multiply the volume by
0.25 mL to 3 mL PEG/NaCl for 12 mL amplification) was added, mixed,
and incubated on ice for 30 minutes.
The cells were then centrifuged at 10,500 g for 15 min at 4.degree.
C. in a JSP-F50C centrifuge. The supernatant was removed, and the
phage pellet was resuspended in a total of 1 mL of PBT
(1.times.PBS, 0.05% Tween.RTM. 20, 0.5% BSA) by pipetting.
The sample was transferred to an Eppendorf tube, vortexed, and
centrifuged at 12,000 rpm for 30 sec. The supernatant was
transferred to a clean Eppendorf tube and stored at 4.degree. C.
This amplified phage sample (250-500 .mu.L) was used for the next
round of screening.
Example 3
Preparation of Cultures from Individual Colonies
Ninety-six (96) wells of a deep well plate were filled with 1 mL of
2YT broth/Ampicillin-50/0.1% glucose. Ninety-six (96) colonies were
placed into the wells using P20 tips. The tips were left in the
wells to mark the position. The tips were removed using a
multi-channel pipette after the entire plate was completed. The
plate was covered with a breathable film.
The inoculated plate(s) were incubated in a shaker at 37.degree. C.
until the cultures became turbid, typically within 4 h at 250
rpm.
The plate(s) was removed from the Incubator and 50 .mu.L of the
culture from each well was removed to another deep well block
designated as the "Archive Block" containing 1 mL of 2YT
broth/Ampicillin-50/0.1% glucose. The plate(s) were covered with a
breathable film and incubated overnight at 37.degree. C. and 250
rpm.
After incubating overnight, M13K07 helper phage was added to
2.times.10.sup.10 pfu/mL in 2YT broth/Ampicillin-50/0.1% glucose
(make 6.0 mL per block). Fifty (50) .mu.L of the diluted M13K07 was
added to each culture well in the deep well block. The deep well
block was covered with breathable film and incubated for 30 min at
37.degree. C. and 250 rpm.
Kanamycin was diluted to 0.5 mg/ml and arabinose to 0.4% in 2YT
broth/Ampicillin-50/0.1% glucose (make 6.0 ml per block) and 50
.mu.L was added to each well. The plate was covered with a
breathable film and incubated overnight at 37.degree. C. and 250
rpm.
The "Archive Block" culture was removed from the incubator and 50
.mu.L was transferred to a 96-well plate containing 50 .mu.L of 50%
glycerol. The plate was sealed with foil and stored at -80.degree.
C. The remaining culture in the block was covered with a foil seal
and stored at 4.degree. C.
The block was centrifuged and inoculated with M13K07 at 4000 rpm
for 15 min. While avoiding the bacterial pellet, 850 .mu.L of the
phage supernatant was transferred to a fresh deep well plate,
covered with a foil seal, and stored at 4.degree. C.
Example 4
ELISA Protocol for Fc-Fusions
For each block to be assayed, a 1.times.96 well ELISA plate was
coated with Fc-fusion (1 .mu.g/mL in PBS) at 50 .mu.L/well. The
wells were incubated at 25.degree. C. for at least 1 h.
The Fc-fusion was removed from each well. Three-hundred (300) .mu.L
of blocking buffer (1.times.PBS, 1% BSA) was added to each well of
a receptor-coated plate. Also, 300 .mu.L of the blocking buffer was
added to a separate uncoated 96-well ELISA plate to be used as the
negative control. Both plates were covered with film and left at
37.degree. C. for 1 h or overnight at 4.degree. C.
The plate was washed 4 times with PT (1.times.PBS, 0.05% Tween.RTM.
20) buffer.
Fifty (50) .mu.L of PBT was added to each well. Fifty (50) .mu.L of
the phage supernatant from the block was added to each well and
incubated at 4.degree. C. for 1 h.
The plates were washed 4 times with cold PT.
To each well 100 .mu.L of anti-M13-HRP antibody diluted 1:5000 in
cold PBT was added. The wells were incubated for 1 h at 4.degree.
C.
The plates were then washed 4 times with cold PT.
Fifty (50) .mu.L of TMB was then added to each well, and the wells
were incubated for 1-10 min at 25.degree. C. Fifty (50) .mu.L of a
"stop" solution was added and the plate read at 450 nm.
Example 5
Evaluation of Peptide Heteromer Ability to Activate IL-2 Responsive
Cells
Following the identification of peptidyl ligands that exhibit
IL-2R.alpha. binding activity, compounds will be identified that
exhibit IL-2R agonist, IL-2R antagonist activity, and/or IL-2R
binding activity. This can involve assessing the ability of the
peptide to polymerize the IL-2R.alpha..beta..gamma.c subunits and
to signal in cell-based assays. Polymerization is a necessary, but
not sufficient, step in the activation of IL-2 receptor signaling.
To assess agonist activity in cell-based assays, IL-2 responsive
cell lines will be tested for an indicator of IL-2 signaling,
phosphorylation of STAT5. Compounds that exhibit IL-2R agonist
activity in these cell lines will then be tested in primary human
peripheral blood mononuclear cells (PBMC) for IL-2R agonism, and
for the desired selectivity favoring activation of cell types
expressing IL-2R.beta..gamma.c subunits.
Polymerization potential will be assessed using a .beta.-Gal
complementation system in which a portion of the intracellular
domains of each respective IL-2 receptor subunit is replaced with
functionally complementary fragments of .beta.-Gal, which regain
catalytic activity when brought into sufficiently proximity. Cells
expressing these constructs generate .beta.-Gal activity, with an
EC50 of about 26 nM, when treated with IL-2 (see DiscoverX product
specifications). Candidate compounds will be scored for induction
of STAT5 phosphorylation in two cell lines: (1) CTLL-2 cells, a
mouse cytotoxic T-lymphocyte line that expresses all three IL-2
receptor subunits, and which are responsive to
IL-2R.beta..gamma.c-biased variants as well as wild type IL-2; and
(2) TF-1.beta. cells derived from the human erythroleukemia line
TF-1, which naturally express only IL-2R.gamma.c, and are
engineered to be IL-2 responsive by transfection of IL-2R.beta..
TF-1.beta. will be constructed and IL-2R subunit expression levels
in both cell lines will be verified by QPCR and FACS analysis.
Compounds will be tested in both cell lines. Dose response assays
will be conducted to determine EC50 of the test compounds and to
compare the test compounds with IL-2 as an indicator of
IL-2R.beta..gamma.c receptor bias. To further characterize subunit
bias, a parallel assay will be run in the presence of a
neutralizing antibody to the human IL-2R.beta. subunit.
As a control to confirm that positive compounds are acting through
stimulation of the IL-2 receptor, the assay will also be done with
cells treated with neutralizing anti-huIL-2R.alpha. antibody. To
determine that compound activity is not due to contamination with
cytokines, test compounds will be treated with neutralizing
antibodies (R&D Systems) against the natural
IL-2R.beta..gamma.c agonists, IL-2 and IL-15.
Compounds exhibiting IL-2R agonist activity in the cell lines will
be tested on human primary immune cells, PBMCs, collected from
individual donors (commercially available from Lonza and others),
and in some cases on purified CD4+CD8+ cells (Lonza). A substantial
fraction of PBMCs from normal donors are responsive to IL-2. To
assess IL-2 agonist activity of the test compounds, cells will be
exposed to the compounds or IL-2 and scored for STAT5
phosphorylation by western blot analysis. As a control to confirm
that positive compounds are acting through direct stimulation of
the IL-2 receptor, the assay will also be done with cells treated
with neutralizing anti-huR.alpha. antibody.
Those compounds exhibiting STAT5 activation of PBMCs will be
subjected to a follow-on assay designed to assess subunit bias of
the compounds compared to IL-2. This assay will involve determining
a dose response of the test compounds and IL-2 (1 to 1000 I) over
30 min, scored by a FACS-based protocol allowing detection of both
intracellular pSTAT5 as an indicator of IL-2R activation, and cell
surface CD25, the IL-2R.beta. subunit. Cells expressing the three
IL-2R subunits, IL-2R.alpha..beta..gamma.c, bind IL-2 with very
high affinity (about 10 .mu.M) and are therefore sensitive to low
concentrations of IL-2; whereas cells expressing only
IL-2R.beta..gamma.c (about 1 nM affinity) require exposure to
substantially higher IL-2 levels for activation. Because compounds
provided by the present disclosure are selected for binding to the
IL-2R.alpha. the potency of the compounds comprising an
IL-2R.alpha. ligand is expected to be correlated with the level of
expression of IL-2R.alpha. on cells; and comparison of response
profiles of cells treated with compounds provided by the present
disclosure or treated with IL-2 should reveal any bias.
Example 6
Identified Peptides
Stochastic libraries with each library containing approximately 10
billion independent recombinants, with each clone potentially
displaying a unique peptide sequence have been screened for binding
to the human IL-2R.alpha. subunit. In screening these initial
libraries against the IL-2R.alpha. subunit extracellular domain
(ECD), unique peptide clones were identified and confirmed as
ligands of IL-2R.alpha.. These IL-2R.alpha. ligands can be grouped
into sequence families that exhibit a clear consensus sequence.
Example 7
Chemical Synthesis of IL-2R.alpha..Ligands
2-Cholorotrityl resin (1 g, 1.5 mmole/g, from Anaspec) was washed
with DMF (2.times.), and then allowed to stand in 50 mL DMF for 10
min. The swollen resin was treated with an activated solution of
Fmoc-glycine prepared from 5 eq. of amino acid and 5 eq. of HATU
dissolved at 0.5M in DMF, followed by the addition of 10 eq. of
DIEA, and the mixture gently stirred for 30 min at 25.degree. C.
The resin was washed (DMF, THF, DCM, and MeOH) and dried to yield
the Fmoc-protected resin. Fmoc groups were then removed by gently
shaking the resin with 30% piperidine in DMF for 20 min, followed
by washing (DMF, THF, DCM, and MeOH), and drying. The resin was
then subjected to repeated cycles of Fmoc-amino acid couplings with
HATU activation and Fmoc removal with piperidine to build a desired
amino acid sequence. Except for examples with four cysteine
residues in the sequence, standard 95% TFA-labile amino acid side
chain protecting groups were used. With compounds with four
cysteines, the two cysteine residues proximal to the resin, Trt
protection was used, and for the two cysteine residues distal to
the resin, Acm protection was used. After Fmoc removal from the
final amino acid of the dimer sequence, in some cases the terminal
amine groups were acylated with acetic anhydride (10 eq.) and DIEA
(20 eq.) in DMF for 20 min, followed by washing as described
above.
The completed peptide was cleaved from the resin by suspension in a
solution of TFA (95 vol %), water (2.5 vol %), and
triisopropylsilane (2.5 vol %) for 3 h at 25.degree. C. The TFA
solution was cooled to 5.degree. C. and poured into Et.sub.2O to
precipitate the peptide. Filtration and drying under reduced
pressure gave the desired peptide. Purification via preparative
HPLC with a C18 column afforded the pure peptide with the two
C-terminal thiol groups in a reduced state. This peptide was
dissolved in 20% DMSO/water (1 mg dry weight peptide/mL) and
allowed to stand at 25.degree. C. for 36 h, and then purified by
reverse phase HPLC to provide the peptide with the two C-terminal
thiols linked by a disulfide bridge. In compounds containing four
cysteines, the two N-terminal Acm-protected cysteine residues were
then deprotected by dissolving 0.1 mmole of peptide in 25 mL of 50%
acetic acid/H.sub.2O and 2.5 mL of 1M HCl and adding 5 mL of 0.1M
iodine (in glacial acetic acid; 5 eq.) dropwise with stirring under
a nitrogen atmosphere. The deprotection/oxidation reaction was
allowed to proceed for 2 h at 25.degree. C. with frequent
monitoring (analytical HPLC) to ensure complete reaction. The
reaction was stopped by addition of ice-cooled diethyl ether (9
volume eq.). The resulting solution was cooled on dry ice (3 min),
the ether solution carefully decanted, and the resulting
light-yellow solid purified by preparative reverse phase HPLC (95%)
to yield the final IL-2R.alpha. ligand or peptide having an
IL-2R.alpha. ligand.
IL-2R.alpha. ligands having SEQ ID NO: 400 to SEQ ID NO: 423 were
synthesized.
ASPECTS OF THE INVENTION
The invention is further defined by the following aspects.
Aspect 1. An IL-2R.alpha. ligand, wherein the IL-2R.alpha. ligand
binds to the human IL-2R.alpha. subunit with an IC.sub.50 of less
than 100 .mu.M.
Aspect 2. The IL-2R.alpha. ligand of aspect 1, wherein the
IL-2R.alpha. ligand comprises from 5 to 30 amino acids.
Aspect 3. The IL-2R.alpha. ligand of any one of aspects 1 to 2,
wherein the IL-2R.alpha. ligand binds to the human IL-2R.alpha.
subunit with an IC.sub.50 from 1 .mu.M to 100 .mu.M.
Aspect 4. The IL-2R.alpha. ligand of any one of aspects 1 to 2,
wherein the IL-2R.alpha. ligand binds to the human IL-2R.alpha.
subunit with an IC.sub.50 from 0.1 .mu.M to 50 .mu.M.
Aspect 5. The IL-2R.alpha. ligand of any one of aspects 1 to 2,
wherein the IL-2R.alpha. ligand binds to the human IL-2R.alpha.
subunit with an IC.sub.50 of less than 100 .mu.M.
Aspect 6. The IL-2R.alpha. ligand of any one of aspects 1 to 2,
wherein the IL-2R.alpha. ligand binds to a mammalian IL-2R.alpha.
subunit with an IC.sub.50 of less than 100 .mu.M.
Aspect 7. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises the amino acid sequence
of Formula (1) (SEQ ID NO: 1):
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12-- (1)
wherein, X.sup.1 is selected from an amino acid comprising a large
hydrophobic side chain or an aromatic side chain; X.sup.2 is
selected from an amino acid comprising a large hydrophobic side
chain; X.sup.3 is selected from an amino acid; X.sup.4 is selected
from an amino acid comprising a large hydrophobic side chain;
X.sup.5 is selected from an amino acid comprising a small
hydrophobic side chain or a polar/neutral side chain; X.sup.6 is
selected from an amino acid comprising a large hydrophobic side
chain; X.sup.7 is selected from an amino acid comprising a large
hydrophobic side chain; X.sup.8 is selected from an amino acid
comprising a large hydrophobic side chain; X.sup.9 is selected from
an amino acid comprising a small hydrophobic side chain; X.sup.10
is selected from an amino acid comprising a polar/neutral side
chain; X.sup.11 is selected from an amino acid comprising a large
hydrophobic side chain; and X.sup.12 is selected from an amino acid
comprising a large hydrophobic side chain.
Aspect 8. The IL-2R.alpha. ligand of aspect 7, wherein X.sup.1 is
selected from F, H, I, L, M, V, W, and Y.
Aspect 9. The IL-2R.alpha. ligand of any one of aspects 7 to 8,
wherein X.sup.2 is selected from F, I, L, M, V, W, and Y.
Aspect 10. The IL-2R.alpha. ligand of any one of aspects 7 to 9,
wherein X.sup.3 is selected from A, D, E, F, G, H, I, K, L, M, N,
P, Q, R, S, T, V, W, and Y.
Aspect 11. The IL-2R.alpha. ligand of any one of aspects 7 to 10,
wherein X.sup.4 is selected from F, I, L, M, V, W, and Y.
Aspect 12. The IL-2R.alpha. ligand of any one of aspects 7 to 11,
wherein X.sup.5 is selected from H, N, Q, Y, A, G, P, S, and T.
Aspect 13. The IL-2R.alpha. ligand of any one of aspects 7 to 12,
wherein X.sup.6 is selected from F, I, L, M, V, W, and Y.
Aspect 14. The IL-2R.alpha. ligand of any one of aspects 7 to 13,
wherein X.sup.7 is selected from F, I, L, M, V, W, and Y.
Aspect 15. The IL-2R.alpha. ligand of any one of aspects 7 to 14,
wherein X.sup.8 is selected from F, I, L, M, V, W, and Y.
Aspect 16. The IL-2R.alpha. ligand of any one of aspects 7 to 15,
wherein X.sup.9 is selected from A, G, P, S, and T.
Aspect 17. The IL-2R.alpha. ligand of any one of aspects 7 to 16,
wherein X.sup.10 is selected from H, N, Q, S, T, and Y.
Aspect 18. The IL-2R.alpha. ligand of any one of aspects 7 to 177,
wherein X.sup.11 is selected from F, I, L, M, V, W, and Y.
Aspect 19. The IL-2R.alpha. ligand of any one of aspects 7 to 18,
wherein X.sup.12 is selected from F, I, L, M, V, W, and Y.
Aspect 20. The IL-2R.alpha. ligand of any one of aspects 7 to 19,
wherein X.sup.1 is selected from L, W, and F.
Aspect 21. The IL-2R.alpha. ligand of any one of aspects 7 to 20,
wherein X.sup.2 is selected from D, A, L, and V.
Aspect 22. The IL-2R.alpha. ligand of any one of aspects 7 to 21,
wherein X.sup.3 is selected from L, V, H, P, and E.
Aspect 23. The IL-2R.alpha. ligand of any one of aspects 7 to 22,
wherein X.sup.4 is selected from T, D, and W.
Aspect 24. The IL-2R.alpha. ligand of any one of aspects 7 to 23,
wherein X.sup.5 is selected from Y, W, P, and Q.
Aspect 25. The IL-2R.alpha. ligand of any one of aspects 7 to 24,
wherein X.sup.6 is selected from D, S, V, and A.
Aspect 26. The IL-2R.alpha. ligand of any one of aspects 7 to 25,
wherein X.sup.7 is selected from E and Y.
Aspect 27. The IL-2R.alpha. ligand of any one of aspects 7 to 26,
wherein X.sup.8 is selected from L and F.
Aspect 28. The IL-2R.alpha. ligand of any one of aspects 7 to 27,
wherein X.sup.9 is selected from L, R, and S.
Aspect 29. The IL-2R.alpha. ligand of any one of aspects 7 to 28,
wherein X.sup.10 is selected from A, R, and Q.
Aspect 30. The IL-2R.alpha. ligand of any one of aspects 7 to 29,
wherein X.sup.11 is selected from C, R, V, and M.
Aspect 31. The IL-2R.alpha. ligand of any one of aspects 7 to 30,
wherein X.sup.12 is selected from T, L, and M.
Aspect 32. The IL-2R.alpha. ligand of any one of aspects 7 to 31,
wherein X.sup.1 is F.
Aspect 33. The IL-2R.alpha. ligand of any one of aspects 7 to 32,
wherein X.sup.2 is selected from L and V.
Aspect 34. The IL-2R.alpha. ligand of any one of aspects 7 to 33,
wherein X.sup.3 is selected from A, D, E, F, G, H, I, K, L, M, N,
P, Q, R, S, T, V, W, and Y.
Aspect 35. The IL-2R.alpha. ligand of any one of aspects 7 to 34,
wherein X.sup.4 is W.
Aspect 36. The IL-2R.alpha. ligand of any one of aspects 7 to 35,
wherein X.sup.5 is P.
Aspect 37. The IL-2R.alpha. ligand of any one of aspects 7 to 36,
wherein X.sup.6 is V.
Aspect 38. The IL-2R.alpha. ligand of any one of aspects 7 to 37,
wherein X.sup.7 is Y.
Aspect 39. The IL-2R.alpha. ligand of any one of aspects 7 to 38,
wherein X.sup.8 is F.
Aspect 40. The IL-2R.alpha. ligand of any one of aspects 7 to 39,
wherein X.sup.9 is S.
Aspect 41. The IL-2R.alpha. ligand of any one of aspects 7 to 40,
wherein X.sup.10 is Q.
Aspect 42. The IL-2R.alpha. ligand of any one of aspects 7 to 41,
wherein X.sup.11 is selected from N and V.
Aspect 43. The IL-2R.alpha. ligand of any one of aspects 7 to 42,
wherein X.sup.12 is selected from L and M.
Aspect 44. The IL-2R.alpha. ligand of aspect 7, wherein X.sup.1 is
F, X.sup.4 is W, X.sup.5 is P, X.sup.6, is V, X.sup.7 is Y, X.sup.8
is F, X.sup.9 is S, and X.sup.10 is Q.
Aspect 45. The IL-2R.alpha. ligand of aspect 7,
X.sup.1 is F;
X.sup.2 is selected from F, H, I, L, M, V, W, and Y;
X.sup.3 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.4 is W;
X.sup.5 is selected from H, N, Q, Y, A, G, P, S, and T;
X.sup.6 is V;
X.sup.7 is Y;
X.sup.8 is F;
X.sup.9 is S;
X.sup.10 is Q;
X.sup.11 is selected from F, I, L, M, V, W, and Y; and
X.sup.12 is selected from F, I, L, M, V, W, and Y.
Aspect 46. The IL-2R.alpha. ligand of aspect 7, wherein the
IL-2R.alpha. ligand comprises an amino acid sequence selected from
any one of SEQ ID NO: 2 to SEQ ID NO: 6:
TABLE-US-00027 SEQ ID NO: 2 L D L T Y D E L L A C T SEQ ID NO: 3 W
A Y D W S C F R R R L SEQ ID NO: 4 F L H W P V Y F C Q V M SEQ ID
NO: 5 F L P W P V Y F S Q V L SEQ ID NO: 6 F V E W Q A Y F S Q M
M
Aspect 47. The IL-2R.alpha. ligand of any one of aspects 7 to 46,
wherein,
the amino acid sequence independently comprises from 1 to 4
glycines (G) (SEQ ID NO: 1041) on the N-terminus, on the
C-terminus, or on both the N- and C-termini;
the amino acid sequence comprises a truncated amino acid sequence;
or
the amino acid sequence comprises a truncated amino acid sequence,
wherein the truncated amino acid sequence independently comprises
from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on
the C-terminus, or on both the N- and C-termini.
Aspect 48. The IL-2R.alpha. ligand of aspects 46 to 47, wherein
from 1 to 5 of the amino acids is independently substituted with
another amino acid.
Aspect 49. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises the amino acid sequence
of Formula (2) (SEQ ID NO: 7):
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12-- (2)
wherein, X.sup.1 is selected from an amino acid comprising a large
hydrophobic side chain; X.sup.2 is selected from an amino acid
comprising a large hydrophobic side chain; X.sup.3 is selected from
an amino acid comprising a small hydrophobic side chain; X.sup.4 is
selected from an amino acid comprising a large hydrophobic side
chain; X.sup.5 is selected from an amino acid comprising an acidic
side chain; X.sup.6 is selected from an amino acid comprising an
acidic side chain; X.sup.7 is selected from an amino acid
comprising a large hydrophobic side chain; X.sup.8 is selected from
an amino acid comprising a large hydrophobic side chain; X.sup.9 is
selected from an amino acid; X.sup.10 is selected from an amino
acid comprising a polar/neutral side chain; X.sup.11 is selected
from an amino acid comprising a large hydrophobic side chain; and
X.sup.12 is selected from an amino acid comprising a large
hydrophobic side chain.
Aspect 50. The IL-2R.alpha. ligand of aspect 49, wherein X.sup.1 is
selected from F, I, L, M, V, W, and Y.
Aspect 51. The IL-2R.alpha. ligand of any one of aspects 49 to 50,
wherein X.sup.2 is selected from F, I, L, M, V, W, and Y.
Aspect 52. The IL-2R.alpha. ligand of any one of aspects 49 to 51,
wherein X.sup.3 is selected from A, G, P, S, and T.
Aspect 53. The IL-2R.alpha. ligand of any one of aspects 49 to 52,
wherein X.sup.4 is selected from F, I, L, M, V, W, and Y.
Aspect 54. The IL-2R.alpha. ligand of any one of aspects 49 to 53,
wherein X.sup.6 is selected from D and E.
Aspect 55. The IL-2R.alpha. ligand of any one of aspects 49 to 54,
wherein X.sup.7 is selected from F, I, L, M, V, W, and Y.
Aspect 56. The IL-2R.alpha. ligand of any one of aspects 49 to 55,
wherein X.sup.8 is selected from F, I, L, M, V, W, and Y.
Aspect 57. The IL-2R.alpha. ligand of any one of aspects 49 to 56,
wherein X.sup.9 is selected from A, D, E, F, G, H, I, K, L, M, N,
P, Q, R, S, T, V, W, and Y.
Aspect 58. The IL-2R.alpha. ligand of any one of aspects 49 to 57,
wherein X.sup.10 is selected from H, N, Q, S, T, and Y.
Aspect 59. The IL-2R.alpha. ligand of any one of aspects 49 to 58,
wherein X.sup.11 is selected from F, I, L, M, V, W, and Y.
Aspect 60. The IL-2R.alpha. ligand of any one of aspects 49 to 59,
wherein X.sup.12 is selected from F, I, L, M, V, W, and Y.
Aspect 61. The IL-2R.alpha. ligand of any one of aspects 49 to 60,
wherein X.sup.1 is F.
Aspect 62. The IL-2R.alpha. ligand of any one of aspects 49 to 61,
wherein X.sup.2 is selected from I, L, and V.
Aspect 63. The IL-2R.alpha. ligand of any one of aspects 49 to 62,
wherein X.sup.3 is P.
Aspect 64. The IL-2R.alpha. ligand of any one of aspects 49 to 63,
wherein X.sup.4 is W.
Aspect 65. The IL-2R.alpha. ligand of any one of aspects 49 to 64,
wherein X.sup.5 is selected from P, D, and E.
Aspect 66. The IL-2R.alpha. ligand of any one of aspects 49 to 65,
wherein X.sup.6 is selected from V and E.
Aspect 67. The IL-2R.alpha. ligand of any one of aspects 49 to 66,
wherein X.sup.7 is Y.
Aspect 68. The IL-2R.alpha. ligand of any one of aspects 49 to 67,
wherein X.sup.8 is F.
Aspect 69. The IL-2R.alpha. ligand of any one of aspects 49 to 68,
wherein X.sup.9 is selected from S, A, K, and L.
Aspect 70. The IL-2R.alpha. ligand of any one of aspects 49 to 69,
wherein X.sup.10 is Q.
Aspect 71. The IL-2R.alpha. ligand of any one of aspects 49 to 70,
wherein X.sup.11 is selected from V, I, and L.
Aspect 72. The IL-2R.alpha. ligand of any one of aspects 49 to 71,
wherein X.sup.12 is selected from L and M.
Aspect 73. The IL-2R.alpha. ligand of any one of aspects 49 to 72,
wherein X.sup.1 is F.
Aspect 74. The IL-2R.alpha. ligand of any one of aspects 49 to 73,
wherein X.sup.2 is selected from L and V.
Aspect 75. The IL-2R.alpha. ligand of any one of aspects 49 to 74,
wherein X.sup.3 is P.
Aspect 76. The IL-2R.alpha. ligand of any one of aspects 49 to 75,
wherein X.sup.4 is W.
Aspect 77. The IL-2R.alpha. ligand of any one of aspects 49 to 76,
wherein X.sup.5 is D.
Aspect 78. The IL-2R.alpha. ligand of any one of aspects 49 to 77,
wherein X.sup.6 is E.
Aspect 79. The IL-2R.alpha. ligand of any one of aspects 49 to 78,
wherein X.sup.7 is Y.
Aspect 80. The IL-2R.alpha. ligand of any one of aspects 49 to 79,
wherein X.sup.8 is F.
Aspect 81. The IL-2R.alpha. ligand of any one of aspects 49 to 80,
wherein X.sup.9 is selected from A, D, E, F, G, H, I, K, L, M, N,
P, Q, R, S, T, V, W, and Y.
Aspect 82. The IL-2R.alpha. ligand of any one of aspects 49 to 80,
wherein X.sup.9 is S.
Aspect 83. The IL-2R.alpha. ligand of any one of aspects 49 to 82,
wherein X.sup.10 is Q.
Aspect 84. The IL-2R.alpha. ligand of any one of aspects 49 to 83,
wherein X.sup.11 is selected from I, L, and V.
Aspect 85. The IL-2R.alpha. ligand of any one of aspects 49 to 84,
wherein X.sup.12 is L.
Aspect 86. The IL-2R.alpha. ligand of aspect 49, wherein X.sup.1 is
F, X.sup.3 is P, X.sup.4 is W, X.sup.5 is D,
X.sup.6, is E, X.sup.7 is Y, X.sup.8 is F, X.sup.10 is Q, and
X.sup.12 is L.
Aspect 87. The IL-2R.alpha. ligand of aspect 49, wherein,
X.sup.1 is F;
X.sup.2 is selected from F, I, L, M, V, W, and Y;
X.sup.3 is P;
X.sup.4 is W;
X.sup.5 is selected from D and P;
X.sup.6 is E;
X.sup.7 is Y;
X.sup.8 is F;
X.sup.9 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.10 is Q;
X.sup.11 is selected from F, I, L, M, V, W, and Y; and
X.sup.12 is L.
Aspect 88. The IL-2R.alpha. ligand of aspect 49, wherein the
IL-2R.alpha. ligand comprises an amino acid sequence selected from
any one of SEQ ID NO: 8 to SEQ ID NO: 15:
TABLE-US-00028 SEQ ID NO: 8 F I P W D E Y F A Q L L SEQ ID NO: 9 F
I P W D E Y F K Q V L SEQ ID NO: 10 F V P W D V Y F S Q I L SEQ ID
NO: 11 F I P W D E Y F K Q V L SEQ ID NO: 12 F V P W P E Y F L Q I
M SEQ ID NO: 13 F I P W E E Y F S Q L L SEQ ID NO: 14 F I P W P E Y
F S Q L L SEQ ID NO: 15 F V P W D E Y F L Q I L
Aspect 89. The IL-2R.alpha. ligand of any one of aspects 49 to 88,
wherein,
the amino acid sequence independently comprises from 1 to 4
glycines (G) (SEQ ID NO: 1041) on the N-terminus, on the
C-terminus, or on both the N- and C-termini;
the amino acid sequence comprises a truncated amino acid sequence;
or
the amino acid sequence comprises a truncated amino acid sequence,
wherein the truncated amino acid sequence independently comprises
from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on
the C-terminus, or on both the N- and C-termini.
Aspect 90. The IL-2R.alpha. ligand of any one of aspects 88 to 89,
wherein from 1 to 5 of the amino acids is independently substituted
with another amino acid.
Aspect 91. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises the amino acid sequence
of Formula (3a) (SEQ ID NO: 16), the amino acid sequence of Formula
(3b) (SEQ ID NO: 17), or the amino acid sequence of Formula (3c)
(SEQ ID NO: 18): --X.sup.5--X.sup.6--X.sup.7--X.sup.8-- (3a)
--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--C--X.sup.10--
(3b)
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12-- (3c)
wherein, X.sup.1 is selected from an amino acid comprising a large
hydrophobic side chain; X.sup.2 is selected from an amino acid
comprising a large hydrophobic side chain; X.sup.3 is selected from
an amino acid; X.sup.4 is C; X.sup.5 is selected from an amino acid
comprising a small hydrophobic side chain; X.sup.6 is selected from
an amino acid; X.sup.7 is selected from an amino acid; X.sup.8 is
selected from amino acid comprising a small hydrophobic side chain;
X.sup.9 is C; X.sup.10 is selected from an amino acid comprising a
basic side chain or a polar/neutral side chain; X.sup.11 is
selected from an amino acid comprising a small hydrophobic side
chain; and X.sup.12 is selected from an amino acid.
Aspect 92. The IL-2R.alpha. ligand of aspect 91, wherein X.sup.1 is
selected from F, I, L, M, V, W, and Y.
Aspect 93. The IL-2R.alpha. ligand of any one of aspects 91 to 92,
wherein X.sup.2 is selected from F, I, L, M, V, W, and Y.
Aspect 94. The IL-2R.alpha. ligand of any one of aspects 91 to 93,
wherein X.sup.3 is selected from A, D, E, F, G, H, I, K, L, M, N,
P, Q, R, S, T, V, W, and Y.
Aspect 95. The IL-2R.alpha. ligand of any one of aspects 91 to 94,
wherein X.sup.4 is C.
Aspect 96. The IL-2R.alpha. ligand of any one of aspects 91 to 95,
wherein X.sup.5 is selected from A, G, P, S, and T.
Aspect 97. The IL-2R.alpha. ligand of any one of aspects 91 to 96,
wherein X.sup.6 is selected from A, D, E, F, G, H, I, K, L, M, N,
P, Q, R, S, T, V, W, and Y.
Aspect 98. The IL-2R.alpha. ligand of any one of aspects 91 to 97,
wherein X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M, N,
P, Q, R, S, T, V, W, and Y.
Aspect 99. The IL-2R.alpha. ligand of any one of aspects 91 to 98,
wherein X.sup.8 is selected from A, G, P, S, and T.
Aspect 100. The IL-2R.alpha. ligand of any one of aspects 91 to 99,
wherein X.sup.9 is C.
Aspect 101. The IL-2R.alpha. ligand of any one of aspects 91 to
100, wherein X.sup.10 is selected from H, K, N, Q, R, S, T, and
Y.
Aspect 102. The IL-2R.alpha. ligand of any one of aspects 91 to
101, wherein X.sup.11 is selected from A, G, P, S, and T.
Aspect 103. The IL-2R.alpha. ligand of any one of aspects 91 to
102, wherein X.sup.12 is selected from A, D, E, F, G, H, I, K, L,
M, N, P, Q, R, S, T, V, W, and Y.
Aspect 104. The IL-2R.alpha. ligand of any one of aspects 91 to
103, wherein X.sup.1 is selected from Y and W.
Aspect 105. The IL-2R.alpha. ligand of any one of aspects 91 to
104, wherein X.sup.2 is V.
Aspect 106. The IL-2R.alpha. ligand of any one of aspects 91 to
105, wherein X.sup.3 is selected from M and I.
Aspect 107. The IL-2R.alpha. ligand of any one of aspects 91 to
106, wherein X.sup.4 is C.
Aspect 108. The IL-2R.alpha. ligand of any one of aspects 91 to
107, wherein X.sup.5 is S.
Aspect 109. The IL-2R.alpha. ligand of any one of aspects 91 to
108, wherein X.sup.6 is A.
Aspect 110. The IL-2R.alpha. ligand of any one of aspects 91 to
109, wherein X.sup.7 is F, L, V, and M.
Aspect 111. The IL-2R.alpha. ligand of any one of aspects 91 to
110, wherein X.sup.8 is G.
Aspect 112. The IL-2R.alpha. ligand of any one of aspects 91 to
111, wherein X.sup.9 is C.
Aspect 113. The IL-2R.alpha. ligand of any one of aspects 91 to
112, wherein X.sup.10 is selected from K and R.
Aspect 114. The IL-2R.alpha. ligand of any one of aspects 91 to
113, wherein X.sup.11 is selected from S, P, and A.
Aspect 115. The IL-2R.alpha. ligand of any one of aspects 91 to
114, wherein X.sup.12 is selected from I, L, M, F, and W.
Aspect 116. The IL-2R.alpha. ligand of any one of aspects 91 to
115, wherein X.sup.1 is selected from F, I, L, M, V, W, and Y.
Aspect 117. The IL-2R.alpha. ligand of any one of aspects 91 to
116, wherein X.sup.2 is V.
Aspect 118. The IL-2R.alpha. ligand of any one of aspects 91 to
117, wherein X.sup.3 is selected from F, I, L, M, V, W, and Y.
Aspect 119. The IL-2R.alpha. ligand of any one of aspects 91 to
118, wherein X.sup.4 is C.
Aspect 120. The IL-2R.alpha. ligand of any one of aspects 91 to
119, wherein X.sup.5 is G.
Aspect 121. The IL-2R.alpha. ligand of any one of aspects 91 to
120, wherein X.sup.6 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 122. The IL-2R.alpha. ligand of any one of aspects 91 to
121, wherein X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 123. The IL-2R.alpha. ligand of any one of aspects 91 to
122, wherein X.sup.8 is G.
Aspect 124. The IL-2R.alpha. ligand of any one of aspects 91 to
123, wherein X.sup.9 is C.
Aspect 125. The IL-2R.alpha. ligand of any one of aspects 91 to
124, wherein X.sup.10 is R.
Aspect 126. The IL-2R.alpha. ligand of any one of aspects 91 to
125, wherein X.sup.11 is S.
Aspect 127. The IL-2R.alpha. ligand of any one of aspects 91 to
126, wherein X.sup.12 is selected from F, I, L, M, V, W, and Y.
Aspect 128. The IL-2R.alpha. ligand of any one of aspects 91 to
126, wherein X.sup.12 is V.
Aspect 129. The IL-2R.alpha. ligand of aspect 91, wherein X.sup.2
is V, X.sup.4 is C, X.sup.5 is G, X.sup.8 is G,
X.sup.9 is C, X.sup.10 is R, and X.sup.11 is S.
Aspect 130. The IL-2R.alpha. ligand of aspect 91, wherein,
X.sup.1 is selected from F, I, L, M, V, W, and Y;
X.sup.2 is V;
X.sup.3 is selected from F, I, L, M, V, W, and Y;
X.sup.4 is C;
X.sup.5 is G;
X.sup.6 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.8 is G;
X.sup.9 is C;
X.sup.10 is R;
X.sup.11 is S; and
X.sup.12 is selected from F, I, L, M, V, W, and Y.
Aspect 131. The IL-2R.alpha. ligand of aspect 91, wherein the
IL-2R.alpha. ligand comprises an amino acid sequence selected from
any one of SEQ ID NO: 19 to SEQ ID NO: 24:
TABLE-US-00029 SEQ ID NO: 19 F V L C G L Q G C R G S SEQ ID NO: 20
K V I C G W D G C R SEQ ID NO: 21 L V F C G K N G C H S G SEQ ID
NO: 22 V V L C T P K G C R S A SEQ ID NO: 23 Y V M C S A F G C K S
I SEQ ID NO: 24 F V H C T L L G C W S G
Aspect 132. The IL-2R.alpha. ligand of any one of aspects 91 to
131, wherein,
the amino acid sequence independently comprises from 1 to 4
glycines (G) (SEQ ID NO: 1041) on the N-terminus, on the
C-terminus, or on both the N- and C-termini;
the amino acid sequence comprises a truncated amino acid sequence;
or
the amino acid sequence comprises a truncated amino acid sequence,
wherein the truncated amino acid sequence independently comprises
from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on
the C-terminus, or on both the N- and C-termini.
Aspect 133. The IL-2R.alpha. ligand of any one of aspects 131 to
132, wherein from 1 to 5 of the amino acids is independently
substituted with another amino acid.
Aspect 134. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises the amino acid sequence
of Formula (4a) (SEQ ID NO: 25), the amino acid sequence of Formula
(4b) (SEQ ID NO: 26), the amino acid sequence of Formula (4c) (SEQ
ID NO: 27), or the amino acid sequence of Formula (4d) (SEQ ID NO:
28): --X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9-- (4a)
--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--C--X.sup.10--
(4b)
--X.sup.2--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--C--X.sup.10--X-
.sup.11-- (4c)
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12-- (4d)
wherein, X.sup.1 is selected from an amino acid comprising a large
hydrophobic side chain; X.sup.2 is selected from an amino acid
comprising a large hydrophobic side chain; X.sup.3 is selected from
an amino acid comprising a large hydrophobic side chain; X.sup.4 is
C; X.sup.5 is selected from an amino acid comprising a small
hydrophobic side chain; X.sup.6 is selected from an amino acid
comprising a small hydrophobic side chain; X.sup.7 is selected from
an amino acid comprising a large hydrophobic side chain; X.sup.8 is
selected from an amino acid comprising a small hydrophobic side
chain; X.sup.9 is C; X.sup.10 is selected from an amino acid
comprising a basic side chain; X.sup.11 is selected from an amino
acid comprising a small hydrophobic side chain; and X.sup.12 is
selected from an amino acid comprising a large hydrophobic side
chain.
Aspect 135. The IL-2R.alpha. ligand of aspect 134, wherein X.sup.1
is selected from F, I, L, M, V, W, and Y.
Aspect 136. The IL-2R.alpha. ligand of any one of aspects 134 to
135, wherein X.sup.2 is selected from F, I, L, M, V, W, and Y.
Aspect 137. The IL-2R.alpha. ligand of any one of aspects 134 to
136, wherein X.sup.3 is selected from F, I, L, M, V, W, and Y.
Aspect 138. The IL-2R.alpha. ligand of any one of aspects 134 to
137, wherein X.sup.4 is C.
Aspect 139. The IL-2R.alpha. ligand of any one of aspects 134 to
138, wherein X.sup.5 is selected from A, G, P, S, and T.
Aspect 140. The IL-2R.alpha. ligand of any one of aspects 134 to
139, wherein X.sup.6 is selected from A, G, P, S, and T.
Aspect 141. The IL-2R.alpha. ligand of any one of aspects 134 to
140, wherein X.sup.7 is selected from F, I, L, M, V, W, and Y.
Aspect 142. The IL-2R.alpha. ligand of any one of aspects 134 to
141, wherein X.sup.8 is selected from A, G, P, S, and T.
Aspect 143. The IL-2R.alpha. ligand of any one of aspects 134 to
142, wherein X.sup.9 is C.
Aspect 144. The IL-2R.alpha. ligand of any one of aspects 134 to
143, wherein X.sup.10 is selected from H, K, and R.
Aspect 145. The IL-2R.alpha. ligand of any one of aspects 134 to
144, wherein X.sup.11 is selected from A, G, P, S, and T.
Aspect 146. The IL-2R.alpha. ligand of any one of aspects 134 to
145, wherein X.sup.12 is selected from F, I, L, M, V, W, and Y.
Aspect 147. The IL-2R.alpha. ligand of any one of aspects 134 to
146, wherein X.sup.1 is selected from Y and W.
Aspect 148. The IL-2R.alpha. ligand of any one of aspects 134 to
147, wherein X.sup.2 is V.
Aspect 149. The IL-2R.alpha. ligand of any one of aspects 134 to
148, wherein X.sup.3 is selected from M and I.
Aspect 150. The IL-2R.alpha. ligand of any one of aspects 134 to
149, wherein X.sup.4 is C.
Aspect 151. The IL-2R.alpha. ligand of any one of aspects 134 to
150, wherein X.sup.5 is S.
Aspect 152. The IL-2R.alpha. ligand of any one of aspects 134 to
151, wherein X.sup.6 is A.
Aspect 153. The IL-2R.alpha. ligand of any one of aspects 134 to
152, wherein X.sup.7 is selected from F, L, V, and M.
Aspect 154. The IL-2R.alpha. ligand of any one of aspects 134 to
153, wherein X.sup.8 is G.
Aspect 155. The IL-2R.alpha. ligand of any one of aspects 134 to
154, wherein X.sup.9 is C.
Aspect 156. The IL-2R.alpha. ligand of any one of aspects 134 to
155, wherein X.sup.10 is selected from R and K.
Aspect 157. The IL-2R.alpha. ligand of any one of aspects 134 to
156, wherein X.sup.11 is selected from S, P, and A.
Aspect 158. The IL-2R.alpha. ligand of any one of aspects 134 to
157, wherein X.sup.12 is selected from I, M, F, and W.
Aspect 159. The IL-2R.alpha. ligand of any one of aspects 134 to
158, wherein X.sup.1 is W.
Aspect 160. The IL-2R.alpha. ligand of any one of aspects 134 to
159, wherein X.sup.2 is V.
Aspect 161. The IL-2R.alpha. ligand of any one of aspects 134 to
160, wherein X.sup.3 is I.
Aspect 162. The IL-2R.alpha. ligand of any one of aspects 134 to
161, wherein X.sup.4 is C.
Aspect 163. The IL-2R.alpha. ligand of any one of aspects 134 to
162, wherein X.sup.5 is S
Aspect 164. The IL-2R.alpha. ligand of any one of aspects 134 to
163, wherein X.sup.6 is A.
Aspect 165. The IL-2R.alpha. ligand of any one of aspects 134 to
164, wherein X.sup.7 is selected from F, I, L, M, V, W, and Y.
Aspect 166. The IL-2R.alpha. ligand of any one of aspects 134 to
165, wherein X.sup.8 is G.
Aspect 167. The IL-2R.alpha. ligand of any one of aspects 134 to
166, wherein X.sup.9 is C.
Aspect 168. The IL-2R.alpha. ligand of any one of aspects 134 to
167, wherein X.sup.10 is R.
Aspect 169. The IL-2R.alpha. ligand of any one of aspects 134 to
168, wherein X.sup.11 is S.
Aspect 170. The IL-2R.alpha. ligand of any one of aspects 134 to
169, wherein X.sup.12 is selected from F, I, L, M, V, W, and Y.
Aspect 171. The IL-2R.alpha. ligand of aspect 134, wherein X.sup.1
is W, X.sup.2 is V, X.sup.3 is I, X.sup.4 is C, X.sup.5 is S,
X.sup.6 is A, X.sup.8 is G, X.sup.9 is C, X.sup.10 is R, and
X.sup.11 is S.
Aspect 172. The IL-2R.alpha. ligand of aspect 134, wherein,
X.sup.1 is W;
X.sup.2 is V;
X.sup.3 is I;
X.sup.4 is C;
X.sup.5 is S;
X.sup.6 is A;
X.sup.7 is selected from F, I, L, M, V, W, and Y.
X.sup.8 is G;
X.sup.9 is C;
X.sup.10 is selected from R and K;
X.sup.11 is S; and
X.sup.12 is selected from F, I, L, M, V, W, and Y.
Aspect 173. The IL-2R.alpha. ligand of aspect 134, wherein the
IL-2R.alpha. ligand comprises an amino acid sequence selected from
any one of SEQ ID NO: 29 to SEQ ID NO: 36:
TABLE-US-00030 SEQ ID NO: 29 W V I C S A L G C R S L SEQ ID NO: 30
W V I C S A L G C R S M SEQ ID NO: 31 W V I C S A V G C R P F SEQ
ID NO: 32 W V I C S A M G C R S I SEQ ID NO: 33 W V I C S A L G C R
S I SEQ ID NO: 34 W V I C S A F G C R S M SEQ ID NO: 35 W V I C S A
L G C R P F SEQ ID NO: 36 W V I C S A L G C K A W
Aspect 174. The IL-2R.alpha. ligand of any one of aspects 134 to
173, wherein,
the amino acid sequence independently comprises from 1 to 4
glycines (G) (SEQ ID NO: 1041) on the N-terminus, on the
C-terminus, or on both the N- and C-termini;
the amino acid sequence comprises a truncated amino acid sequence;
or
the amino acid sequence comprises a truncated amino acid sequence,
wherein the truncated amino acid sequence independently comprises
from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on
the C-terminus, or on both the N- and C-termini.
Aspect 175. The IL-2R.alpha. ligand of any one of aspects 173 to
174, wherein from 1 to 5 of the amino acids is independently
substituted with another amino acid.
Aspect 176. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises the amino acid sequence
of Formula (5a) (SEQ ID NO: 37), the amino acid sequence of Formula
(5b) (SEQ ID NO: 38), the amino acid sequence of Formula (5c) (SEQ
ID NO: 39), or the amino acid sequence of Formula (5d) (SEQ ID NO:
40): --X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9-- (5a)
--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--C--X.sup.11--
(5b)
--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--C--X.sup.-
11--X.sup.12-- (5c)
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12-- (5d)
wherein, X.sup.1 is selected from an amino acid comprising an
aromatic side chain or a large hydrophobic side chain; X.sup.2 is
selected from an amino acid comprising a large hydrophobic side
chain; X.sup.3 is selected from an amino acid comprising a large
hydrophobic side chain; X.sup.4 is C; X.sup.5 is selected from an
amino acid comprising a small hydrophobic side chain or an acidic
side chain; X.sup.6 is selected from an amino acid; X.sup.7 is
selected from an amino acid; X.sup.8 is selected from an amino
acid; X.sup.9 is selected from an amino acid comprising a small
hydrophobic side chain; X.sup.10 is C; X.sup.11 is selected from an
amino acid comprising a basic side chain; and X.sup.12 is selected
from an amino acid.
Aspect 177. The IL-2R.alpha. ligand of aspect 176, wherein X.sup.1
is selected from F, H, I, L, M, V, W, and Y.
Aspect 178. The IL-2R.alpha. ligand of any one of aspects 176 to
177, wherein X.sup.2 is selected from F, I, L, M, V, W, and Y.
Aspect 179. The IL-2R.alpha. ligand of any one of aspects 176 to
178, wherein X.sup.3 is selected from F, I, L, M, V, W, and Y.
Aspect 180. The IL-2R.alpha. ligand of any one of aspects 176 to
179, wherein X.sup.4 is C.
Aspect 181. The IL-2R.alpha. ligand of any one of aspects 176 to
180, wherein X.sup.5 is selected from A, G, H, K, P, R, S, and
T.
Aspect 182. The IL-2R.alpha. ligand of any one of aspects 176 to
181, wherein X.sup.6 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 183. The IL-2R.alpha. ligand of any one of aspects 176 to
182, wherein X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 184. The IL-2R.alpha. ligand of any one of aspects 176 to
183, wherein X.sup.8 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 185. The IL-2R.alpha. ligand of any one of aspects 176 to
184, wherein X.sup.9 is selected from A, G, P, S, and T.
Aspect 186. The IL-2R.alpha. ligand of any one of aspects 176 to
185, wherein X.sup.10 is C.
Aspect 187. The IL-2R.alpha. ligand of any one of aspects 176 to
186, wherein X.sup.11 is selected from H, K, and R.
Aspect 188. The IL-2R.alpha. ligand of any one of aspects 176 to
187, wherein X.sup.12 is selected from A, D, E, F, G, H, I, K, L,
M, N, P, Q, R, S, T, V, W, and Y.
Aspect 189. The IL-2R.alpha. ligand of any one of aspects 176 to
188, wherein X.sup.1 is selected from F, H, W, and Y.
Aspect 190. The IL-2R.alpha. ligand of any one of aspects 176 to
189, wherein X.sup.2 is V.
Aspect 191. The IL-2R.alpha. ligand of any one of aspects 176 to
190, wherein X.sup.3 is selected from F, I, L, M, V, W, and Y.
Aspect 192. The IL-2R.alpha. ligand of any one of aspects 176 to
191, wherein X.sup.4 is selected from F, K, L, V, W, and H.
Aspect 193. The IL-2R.alpha. ligand of any one of aspects 176 to
192, wherein X.sup.5 is V.
Aspect 194. The IL-2R.alpha. ligand of any one of aspects 176 to
193, wherein X.sup.5 is selected from L, F, M, H, T, A, and I.
Aspect 195. The IL-2R.alpha. ligand of any one of aspects 176 to
194, wherein X.sup.5 is C.
Aspect 196. The IL-2R.alpha. ligand of any one of aspects 176 to
195, wherein X.sup.6 is selected from G, T, S, R, and K.
Aspect 197. The IL-2R.alpha. ligand of any one of aspects 176 to
196, wherein X.sup.6 is selected from L, W, K, P, A, N, W, and
V.
Aspect 198. The IL-2R.alpha. ligand of any one of aspects 176 to
197, wherein X.sup.7 is selected from Q, D, N, K, F, L, R, G, and
D,
Aspect 199. The IL-2R.alpha. ligand of any one of aspects 176 to
198, wherein X.sup.8 is selected from G, N, Y, H, and G.
Aspect 200. The IL-2R.alpha. ligand of any one of aspects 176 to
199, wherein X.sup.9 is G.
Aspect 201. The IL-2R.alpha. ligand of any one of aspects 176 to
200, wherein X.sup.10 is C.
Aspect 202. The IL-2R.alpha. ligand of any one of aspects 176 to
201, wherein X.sup.11 is selected from G, S, R, T, and Y.
Aspect 203. The IL-2R.alpha. ligand of any one of aspects 176 to
202, wherein X.sup.12 is selected from S, G, A, I, G, P, R, and
S.
Aspect 204. The IL-2R.alpha. ligand of any one of aspects 176 to
203, wherein X.sup.1 is selected from F, W, and Y.
Aspect 205. The IL-2R.alpha. ligand of any one of aspects 176 to
204, wherein X.sup.2 is V.
Aspect 206. The IL-2R.alpha. ligand of any one of aspects 176 to
205, wherein X.sup.3 is selected from F, I, L, M, V, W, and Y.
Aspect 207. The IL-2R.alpha. ligand of any one of aspects 176 to
206, wherein X.sup.4 is C.
Aspect 208. The IL-2R.alpha. ligand of any one of aspects 176 to
207, wherein X.sup.5 is selected from A, G, P, S, and T.
Aspect 209. The IL-2R.alpha. ligand of any one of aspects 176 to
208, wherein X.sup.5 is selected from H, K, and R.
Aspect 210. The IL-2R.alpha. ligand of any one of aspects 176 to
209, wherein X.sup.5 is S.
Aspect 211. The IL-2R.alpha. ligand of any one of aspects 176 to
210, wherein X.sup.6 is selected from F, I, L, M, V, W, and Y.
Aspect 212. The IL-2R.alpha. ligand of any one of aspects 176 to
211, wherein X.sup.6 is W.
Aspect 213. The IL-2R.alpha. ligand of any one of aspects 176 to
212, wherein X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 214. The IL-2R.alpha. ligand of any one of aspects 176 to
213, wherein X.sup.8 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 215. The IL-2R.alpha. ligand of any one of aspects 176 to
214, wherein X.sup.9 is G.
Aspect 216. The IL-2R.alpha. ligand of any one of aspects 176 to
215, wherein X.sup.10 is C.
Aspect 217. The IL-2R.alpha. ligand of any one of aspects 176 to
216, wherein X.sup.11 is R.
Aspect 218. The IL-2R.alpha. ligand of any one of aspects 176 to
217, wherein X.sup.12 is selected from A, D, E, F, G, H, I, K, L,
M, N, P, Q, R, S, T, V, W, and Y.
Aspect 219. The IL-2R.alpha. ligand of aspect 176, wherein X.sup.2
is V, X.sup.4 is C, X.sup.5 is S, X.sup.9 is G,
X.sup.10 is C, and X.sup.11 is R.
Aspect 220. The IL-2R.alpha. ligand of aspect 176, wherein,
X.sup.1 is selected from F, H, I, L, M, V, W, and Y;
X.sup.2 is V;
X.sup.3 is selected from F, I, L, M, V, W, and Y;
X.sup.4 is C;
X.sup.5 is S;
X.sup.6 is selected from F, I, L, M, V, W, and Y;
X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.8 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.9 is G;
X.sup.10 is C;
X.sup.11 is R; and
X.sup.12 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y.
Aspect 221. The IL-2R.alpha. ligand of aspect 176, wherein the
IL-2R.alpha. ligand comprises an amino acid sequence selected from
any one of SEQ ID NO: 41 to SEQ ID NO: 45:
TABLE-US-00031 SEQ ID NO: 41 Y V L C S N R N G C R P SEQ ID NO: 42
Y V T C R W G Y G C T R SEQ ID NO: 43 W V A C S W D H G C R S SEQ
ID NO: 44 H V I C S V N G G C R G SEQ ID NO: 45 W V X C K P L H G C
Y G
Aspect 222. The IL-2R.alpha. ligand of any one of aspects 176 to
221, wherein,
the amino acid sequence independently comprises from 1 to 4
glycines (G) (SEQ ID NO: 1041) on the N-terminus, on the
C-terminus, or on both the N- and C-termini;
the amino acid sequence comprises a truncated amino acid sequence;
or
the amino acid sequence comprises a truncated amino acid sequence,
wherein the truncated amino acid sequence independently comprises
from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on
the C-terminus, or on both the N- and C-termini.
Aspect 223. The IL-2R.alpha. ligand of any one of aspects 221 to
222, wherein from 1 to 5 of the amino acids is independently
substituted with another amino acid.
Aspect 224. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises the amino acid sequence
of Formula (6a) (SEQ ID NO: 46), the amino acid sequence of Formula
(6b) (SEQ ID NO: 47), the amino acid sequence of Formula (6c) (SEQ
ID NO: 48), or the amino acid sequence of Formula (6d) (SEQ ID NO:
49):
--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.sup.11--
(6a)
--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.su-
p.11--C--X.sup.13-- (6b)
--X.sup.2--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup-
.10--X.sup.11--C--X.sup.13--X.sup.14-- (6c)
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12--X.sup.13--X.sup.14--X.sup.15--
(6d)
wherein, X.sup.1 is selected from an amino acid; X.sup.2 is
selected from an amino acid; X.sup.3 is selected from an amino acid
comprising a large hydrophobic side chain or an aromatic side
chain; X.sup.4 is C; X.sup.5 is selected from an amino acid
comprising a large hydrophobic side chain; X.sup.6 is selected from
an amino acid comprising a basic side chain; X.sup.7 is selected
from an amino acid comprising a small hydrophobic side chain or a
polar neutral side chain; X.sup.8 is selected from an amino acid
comprising an acidic side chain; X.sup.9 is selected from an amino
acid comprising a small hydrophobic side chain; X.sup.10 is
selected from an amino acid; X.sup.11 is selected from an amino
acid comprising a small hydrophobic side chain; X.sup.12 is C;
X.sup.13 is selected from an amino acid comprising an aromatic side
chain or a large hydrophobic side chain; X.sup.14 is selected from
an amino acid comprising a small hydrophobic side chain or a polar
neutral side chain; and X.sup.15 is selected from an amino
acid.
Aspect 225. The IL-2R.alpha. ligand of aspect 224, wherein, X.sup.1
is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,
W, and Y; X.sup.2 is selected from A, D, E, F, G, H, I, K, L, M, N,
P, Q, R, S, T, V, W, and Y; X.sup.3 is selected from F, H, I, L, M,
V, W, and Y; X.sup.4 is C; X.sup.5 is selected from F, I, L, M, V,
W, and Y; X.sup.6 is selected from H, K, and R; X.sup.7 is selected
from A, G, H, N, P, Q, S, T, and Y; X.sup.8 is selected from D and
E; X.sup.9 is selected from A, G, P, S, and T; X.sup.10 is selected
from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y;
X.sup.11 is selected from A, G, P, S, and T; X.sup.12 is C;
X.sup.13 is selected from F, H, I, L, M, V, W, and Y; X.sup.14 is
selected from A, G, H, N, P, Q, S, T, and Y; and X.sup.15 is
selected from any A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T,
V, W, and Y.
Aspect 226. The IL-2R.alpha. ligand f any one of aspects 224 to
225, wherein X.sup.1 is selected from E, K, R, T, and L.
Aspect 227. The IL-2R.alpha. ligand of any one of aspects 224 to
226, wherein X.sup.2 is selected from Q, Y, V, K, and R.
Aspect 228. The IL-2R.alpha. ligand of any one of aspects 224 to
227, wherein X.sup.3 is selected from F, W, V, and L.
Aspect 229. The IL-2R.alpha. ligand of any one of aspects 224 to
228, wherein X.sup.4 is C.
Aspect 230. The IL-2R.alpha. ligand of any one of aspects 224 to
229, wherein X.sup.5 is L.
Aspect 231. The IL-2R.alpha. ligand of any one of aspects 224 to
230, wherein X.sup.6 is selected from V, R, A, and K.
Aspect 232. The IL-2R.alpha. ligand of any one of aspects 224 to
231, wherein X.sup.7 is S.
Aspect 233. The IL-2R.alpha. ligand of any one of aspects 224 to
232, wherein X.sup.8 is selected from D and E.
Aspect 234. The IL-2R.alpha. ligand of any one of aspects 224 to
233, wherein X.sup.9 is P.
Aspect 235. The IL-2R.alpha. ligand of any one of aspects 224 to
234, wherein X.sup.10 is selected from M, D, N, M Q, and T.
Aspect 236. The IL-2R.alpha. ligand of any one of aspects 224 to
235, wherein X.sup.11 is selected from A and S.
Aspect 237. The IL-2R.alpha. ligand of any one of aspects 224 to
236, wherein X.sup.12 is C.
Aspect 238. The IL-2R.alpha. ligand of any one of aspects 224 to
237, wherein X.sup.13 is selected from F and W.
Aspect 239. The IL-2R.alpha. ligand of any one of aspects 224 to
238, wherein X.sup.14 is selected from S, A, and I.
Aspect 240. The IL-2R.alpha. ligand of any one of aspects 224 to
239, wherein X.sup.15 is selected from L, T, M, and V.
Aspect 241. The IL-2R.alpha. ligand of any one of aspects 224 to
240, wherein X.sup.1 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 242. The IL-2R.alpha. ligand of any one of aspects 224 to
241, wherein X.sup.2 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 243. The IL-2R.alpha. ligand of any one of aspects 224 to
242, wherein X.sup.3 is selected from F, W, and Y.
Aspect 244. The IL-2R.alpha. ligand of any one of aspects 224 to
243, wherein X.sup.4 is C.
Aspect 245. The IL-2R.alpha. ligand of any one of aspects 224 to
244, wherein X.sup.5 is L.
Aspect 246. The IL-2R.alpha. ligand of any one of aspects 224 to
245, wherein X.sup.6 is selected from H, K, and R.
Aspect 247. The IL-2R.alpha. ligand of any one of aspects 224 to
246, wherein X.sup.7 is S.
Aspect 248. The IL-2R.alpha. ligand of any one of aspects 224 to
247, wherein X.sup.8 is selected from D and E.
Aspect 249. The IL-2R.alpha. ligand of any one of aspects 224 to
248, wherein X.sup.9 is P.
Aspect 250. The IL-2R.alpha. ligand of any one of aspects 224 to
249, wherein X.sup.10 is selected from A, D, E, F, G, H, I, K, L,
M, N, P, Q, R, S, T, V, W, and Y.
Aspect 251. The IL-2R.alpha. ligand of any one of aspects 224 to
250, wherein X.sup.11 is A.
Aspect 252. The IL-2R.alpha. ligand of any one of aspects 224 to
251, wherein X.sup.12 is C.
Aspect 253. The IL-2R.alpha. ligand of any one of aspects 224 to
252, wherein X.sup.13 is selected from F, W, and Y.
Aspect 254. The IL-2R.alpha. ligand of any one of aspects 224 to
252, wherein X.sup.13 is W.
Aspect 255. The IL-2R.alpha. ligand of any one of aspects 224 to
254, wherein X.sup.14 is S.
Aspect 256. The IL-2R.alpha. ligand of any one of aspects 224 to
255, wherein X.sup.15 is selected from A, D, E, F, G, H, I, K, L,
M, N, P, Q, R, S, T, V, W, and Y.
Aspect 257. The IL-2R.alpha. ligand of aspect 224, wherein X.sup.4
is C, X.sup.5 is L, X.sup.7 is S, X.sup.8 is E, X.sup.9 is P,
X.sup.11 is A, X.sup.12 is C, X.sup.12 is W, and X.sup.14 is S.
Aspect 258. The IL-2R.alpha. ligand of aspect 224, wherein,
X.sup.1 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.2 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.3 is selected from F, H, I, L, M, V, W, and Y;
X.sup.4 is C;
X.sup.5 is L;
X.sup.6 is selected from H, K, and R;
X.sup.7 is S;
X.sup.8 is E;
X.sup.9 is P;
X.sup.10 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.11 is A;
X.sup.12 is C;
X.sup.11 is W;
X.sup.14 is S; and
X.sup.15 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y.
Aspect 259. The IL-2R.alpha. ligand of aspect 224, wherein the
IL-2R.alpha. ligand comprises an amino acid sequence selected from
any one of SEQ ID NO: 50 to SEQ ID NO: 54:
TABLE-US-00032 SEQ ID NO: 50 E Q F C L V S D P M A C W S L SEQ ID
NO: 51 K Y W C L R S E P D A C F A T SEQ ID NO: 52 R V Y C L A S E
P N S C W S T SEQ ID NO: 53 T K L C L K S E P Q A C W S M SEQ ID
NO: 54 I R F C L R S E P T A C W I V
Aspect 260. The IL-2R.alpha. ligand of any one of aspects 224 to
259, wherein,
the amino acid sequence independently comprises from 1 to 4
glycines (G) (SEQ ID NO: 1041) on the N-terminus, on the
C-terminus, or on both the N- and C-termini;
the amino acid sequence comprises a truncated amino acid sequence;
or
the amino acid sequence comprises a truncated amino acid sequence,
wherein the truncated amino acid sequence independently comprises
from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on
the C-terminus, or on both the N- and C-termini.
Aspect 261. The IL-2R.alpha. ligand of any one of aspects 259 to
260, wherein from 1 to 5 of the amino acids is independently
substituted with another amino acid.
Aspect 262. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises the amino acid sequence
of Formula (7a) (SEQ ID NO: 55), the amino acid sequence of Formula
(7b) (SEQ ID NO: 56), the amino acid sequence of Formula (7c) (SEQ
ID NO: 57), or the amino acid sequence of Formula (7d) (SEQ ID NO:
58):
--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.sup.11--
(7a)
--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.su-
p.11--C--X.sup.13-- (7b)
--X.sup.2--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup-
.10--X.sup.11--C--X.sup.13--X.sup.14-- (7c)
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12--X.sup.13--X.sup.14--X.sup.15--
(7d)
wherein, X.sup.1 is selected from a basic amino acid; X.sup.2 is
selected from a basic amino acid; X.sup.3 is selected from an amino
acid comprising a large hydrophobic side chain; X.sup.4 is C;
X.sup.5 is selected from an amino acid comprising a large
hydrophobic side chain; X.sup.6 is selected from an amino acid
comprising a basic side chain; X.sup.7 is selected from an amino
acid comprising a small hydrophobic side chain or a polar neutral
side chain; X.sup.8 is selected from an amino acid comprising a
large hydrophobic side chain; X.sup.9 is selected from an amino
acid comprising a small hydrophobic side chain; X.sup.10 is
selected from an amino acid comprising a small hydrophobic side
chain or a polar neutral side chain; X.sup.11 is selected from an
amino acid comprising a small hydrophobic side chain; X.sup.12 is
C; X.sup.13 is selected from an amino acid comprising an aromatic
side chain or a large hydrophobic side chain; X.sup.14 is selected
from an amino acid comprising a small hydrophobic side chain or a
polar neutral side chain; and X.sup.15 is selected from an amino
acid comprising a large hydrophobic side chain.
Aspect 263. The IL-2R.alpha. ligand of aspect 262, wherein,
X.sup.1 is selected from K, and R;
X.sup.2 is selected from H, K, and R;
X.sup.3 is selected from F, I, L, M, V, W, and Y;
X.sup.4 is C;
X.sup.5 is selected from F, I, L, M, V, W, and Y;
X.sup.6 is selected from H, K, and R;
X.sup.7 is selected from A, G, H, N, P, Q, S, T, and Y;
X.sup.8 is selected from F, I, L, M, V, W, and Y;
X.sup.9 is selected from A, G, P, S, and T;
X.sup.10 is selected from A, G, H, N, P, Q, S, T, and Y;
X.sup.11 is selected from A, G, P, S, and T;
X.sup.12 is C;
X.sup.13 is selected from F, H, I, L, M, V, W, and Y;
X.sup.14 is selected from A, G, H, N, P, Q, S, T, and Y; and
X.sup.15 is selected from F, I, L, M, V, W, and Y.
Aspect 264. The IL-2R.alpha. ligand of any one of aspects 262 to
263, wherein X.sup.1 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 265. The IL-2R.alpha. ligand of any one of aspects 262 to
264, wherein X.sup.2 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 266. The IL-2R.alpha. ligand of any one of aspects 262 to
265, wherein X.sup.3 is selected from F, I, L, M, V, W, and Y.
Aspect 267. The IL-2R.alpha. ligand of any one of aspects 262 to
266, wherein X.sup.4 is C.
Aspect 268. The IL-2R.alpha. ligand of any one of aspects 262 to
267, wherein X.sup.5 is selected from F, I, L, M, V, W, and Y.
Aspect 269. The IL-2R.alpha. ligand of any one of aspects 262 to
268, wherein X.sup.5 is L.
Aspect 270. The IL-2R.alpha. ligand of any one of aspects 262 to
269, wherein X.sup.6 is selected from H, K, and R.
Aspect 271. The IL-2R.alpha. ligand of any one of aspects 262 to
270, wherein X.sup.7 is selected from A, G, P, S, and T.
Aspect 272. The IL-2R.alpha. ligand of any one of aspects 262 to
271, wherein X.sup.7 is selected from H, N, Q, S, T, and Y.
Aspect 273. The IL-2R.alpha. ligand of any one of aspects 262 to
272, wherein X.sup.7 is S.
Aspect 274. The IL-2R.alpha. ligand of any one of aspects 262 to
273, wherein X.sup.8 is selected from D and E.
Aspect 275. The IL-2R.alpha. ligand of any one of aspects 262 to
274, wherein X.sup.9 is P.
Aspect 276. The IL-2R.alpha. ligand of any one of aspects 262 to
275, wherein X.sup.10 is selected from A, D, E, F, G, H, I, K, L,
M, N, P, Q, R, S, T, V, W, and Y.
Aspect 277. The IL-2R.alpha. ligand of any one of aspects 262 to
276, wherein X.sup.11 is A.
Aspect 278. The IL-2R.alpha. ligand of any one of aspects 262 to
277, wherein X.sup.12 is C.
Aspect 279. The IL-2R.alpha. ligand of any one of aspects 262 to
278, wherein X.sup.13 is W.
Aspect 280. The IL-2R.alpha. ligand of any one of aspects 262 to
279, wherein X.sup.14 is S.
Aspect 281. The IL-2R.alpha. ligand of any one of aspects 262 to
280, wherein X.sup.15 is selected from A, D, E, F, G, H, I, K, L,
M, N, P, Q, R, S, T, V, W, and Y.
Aspect 282. The IL-2R.alpha. ligand of any one of aspects 262 to
281, wherein X.sup.1 is R.
Aspect 283. The IL-2R.alpha. ligand of any one of aspects 262 to
282, wherein X.sup.2 is R.
Aspect 284. The IL-2R.alpha. ligand of any one of aspects 262 to
283, wherein X.sup.3 is F.
Aspect 285. The IL-2R.alpha. ligand of any one of aspects 262 to
284, wherein X.sup.4 is C.
Aspect 286. The IL-2R.alpha. ligand of any one of aspects 262 to
285, wherein X.sup.5 is L.
Aspect 287. The IL-2R.alpha. ligand of any one of aspects 262 to
286, wherein X.sup.6 is R.
Aspect 288. The IL-2R.alpha. ligand of any one of aspects 262 to
287, wherein X.sup.7 is S.
Aspect 289. The IL-2R.alpha. ligand of any one of aspects 262 to
288, wherein X.sup.8 is E.
Aspect 290. The IL-2R.alpha. ligand of any one of aspects 262 to
289, wherein X.sup.9 is P.
Aspect 291. The IL-2R.alpha. ligand of any one of aspects 262 to
290, wherein X.sup.10 is T.
Aspect 292. The IL-2R.alpha. ligand of any one of aspects 262 to
291, wherein X.sup.11 is A.
Aspect 293. The IL-2R.alpha. ligand of any one of aspects 262 to
292, wherein X.sup.12 is C.
Aspect 294. The IL-2R.alpha. ligand of any one of aspects 262 to
293, wherein X.sup.13 is W.
Aspect 295. The IL-2R.alpha. ligand of any one of aspects 262 to
294, wherein X.sup.14 is T.
Aspect 296. The IL-2R.alpha. ligand of any one of aspects 262 to
295, wherein X.sup.15 is V.
Aspect 297. The IL-2R.alpha. ligand of aspect 262, wherein X.sup.1
is R, X.sup.2 is R, X.sup.3 is F, X.sup.4 is C, X.sup.5 is L,
X.sup.6, is R, X.sup.7 is S, X is E, X.sup.9 is P, X.sup.10 is T,
X.sup.11 is A, X.sup.12 is C, X.sup.11 is W, and X.sup.15 is V.
Aspect 298. The IL-2R.alpha. ligand of aspect 262, wherein,
X.sup.1 is selected from K and R;
X.sup.2 is R;
X.sup.3 is F;
X.sup.4 is C;
X.sup.5 is L;
X.sup.6 is R;
X.sup.7 is S;
X.sup.8 is E;
X.sup.9 is P;
X.sup.10 is T;
X.sup.11 is A;
X.sup.12 is C;
X.sup.13 is W;
X.sup.14 is T; and
X.sup.15 is V.
Aspect 299. The IL-2R.alpha. ligand of aspect 262, wherein the
IL-2R.alpha. ligand comprises an amino acid sequence selected from
any one of SEQ ID NO: 59 to SEQ ID NO: 68:
TABLE-US-00033 SEQ ID NO: 59 R R F C L R S E P T A C W I V SEQ ID
NO: 60 K L F C L R S G D R A C W V V SEQ ID NO: 61 M R F C L R S E
P T A C W T V SEQ ID NO: 62 R R F C L R S E P T A C W D V SEQ ID
NO: 63 R R F C L R S D P T A C W I V SEQ ID NO: 64 K R F C L R S E
P T A C W T V SEQ ID NO: 65 R R F C L R S E P M A C W T V SEQ ID
NO: 66 R R F C L R S E P T A C W T V SEQ ID NO: 67 R R F C L R S E
P A A C W F V SEQ ID NO: 68 R R F C L R S E P T A C W Y V
Aspect 300. The IL-2R.alpha. ligand of any one of aspects 262 to
299, wherein,
the amino acid sequence independently comprises from 1 to 4
glycines (G) (SEQ ID NO: 1041) on the N-terminus, on the
C-terminus, or on both the N- and C-termini;
the amino acid sequence comprises a truncated amino acid sequence;
or
the amino acid sequence comprises a truncated amino acid sequence,
wherein the truncated amino acid sequence independently comprises
from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on
the C-terminus, or on both the N- and C-termini.
Aspect 301. The IL-2R.alpha. ligand of any one of aspects 299 to
300, wherein from 1 to 5 of the amino acids is independently
substituted with another amino acid.
Aspect 302. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises the amino acid sequence
of Formula (8a) (SEQ ID NO: 69), the amino acid sequence of Formula
(8b) (SEQ ID NO: 70), or the amino acid sequence of Formula (8c)
(SEQ ID NO: 71):
--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.sup.1-
1-- (8a)
--X.sup.2--C--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup-
.9--X.sup.10--X.sup.11--C--X.sup.13-- (8b)
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12--X.sup.13--X.sup.14--
(8c)
wherein, X.sup.1 is selected from an amino acid; X.sup.2 is
selected from an amino acid comprising a basic side chain; X.sup.3
is C; X.sup.4 is selected from an amino acid comprising a large
hydrophobic side chain or a basic side chain; X.sup.5 is selected
from an amino acid; X.sup.6 is selected from an amino acid
comprising an acidic side chain; X.sup.7 is selected from an amino
acid; X.sup.8 is selected from an amino acid; X.sup.9 is selected
from an amino acid; X.sup.10 is selected from an amino acid
comprising a small hydrophobic side chain; X.sup.11 is selected
from an amino acid; X.sup.12 is C; X.sup.13 is selected from an
amino acid comprising a large hydrophobic side chain; and X.sup.14
is selected from an amino acid comprising a large hydrophobic side
chain.
Aspect 303. The IL-2R.alpha. ligand of aspect 302, wherein,
X.sup.1 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.2 is selected from H, K, and R;
X.sup.3 is C;
X.sup.4 is selected from F, H, I, K, L, M, R, V, W, and Y;
X.sup.5 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.6 is selected from D and E;
X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.8 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.9 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.10 is selected from A, G, P, S, and T;
X.sup.11 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.12 is C;
X.sup.13 is selected from F, I, L, M, V, W, and Y; and
X.sup.14 is selected from F, I, L, M, V, W, and Y.
Aspect 304. The IL-2R.alpha. ligand of any one of aspects 302 to
303, wherein X.sup.1 is selected from R, I, L, M, N, S, T, V, and
D.
Aspect 305. The IL-2R.alpha. ligand of any one of aspects 302 to
304, wherein X.sup.2 is selected from S, K, R, H, G, and F.
Aspect 306. The IL-2R.alpha. ligand of any one of aspects 302 to
305, wherein X.sup.3 is C.
Aspect 307. The IL-2R.alpha. ligand of any one of aspects 302 to
306, wherein X.sup.4 is selected from N, R, I, T, V, L, and D.
Aspect 308. The IL-2R.alpha. ligand of any one of aspects 302 to
307, wherein X.sup.5 is selected from R, V, L, M, V, G, Y, I, F,
and T.
Aspect 309. The IL-2R.alpha. ligand of any one of aspects 302 to
308, wherein X.sup.5 is selected from Y, L, E, D, S, I, Y, D, and
R.
Aspect 310. The IL-2R.alpha. ligand of any one of aspects 302 to
308, wherein X.sup.6 is selected from Y, L, E, D, S, and R.
Aspect 311. The IL-2R.alpha. ligand of any one of aspects 302 to
310, wherein X.sup.7 is selected from G, E, K, T, P, W, L, Y, G, S,
and R.
Aspect 312. The IL-2R.alpha. ligand of any one of aspects 302 to
311, wherein X.sup.8 is selected from I, A, Q, R, S R, L, N, P, A,
I, R, D, and W.
Aspect 313. The IL-2R.alpha. ligand of any one of aspects 302 to
312, wherein X.sup.9 is selected from W, G, S, D, R, L, F, P, A,
and T.
Aspect 314. The IL-2R.alpha. ligand of any one of aspects 302 to
313, wherein X.sup.10 is selected from G, T, E, W, Q, R, and Y.
Aspect 315. The IL-2R.alpha. ligand of any one of aspects 302 to
314, wherein X.sup.11 is selected from H, P, I, T, H, A, S, F, and
Y.
Aspect 316. The IL-2R.alpha. ligand of any one of aspects 302 to
315, wherein X.sup.12 is C.
Aspect 317. The IL-2R.alpha. ligand of any one of aspects 302 to
316, wherein X.sup.13 is selected from D, V, L, I, Y, I, R, H, T,
I, and W.
Aspect 318. The IL-2R.alpha. ligand of any one of aspects 302 to
317, wherein X.sup.14 is selected from T, S, F, and I.
Aspect 319. The IL-2R.alpha. ligand of any one of aspects 302 to
318, wherein X.sup.1 is selected from R, I, L, M, N, S, T, V, and
D.
Aspect 320. The IL-2R.alpha. ligand of any one of aspects 302 to
319, wherein X.sup.2 is selected from S, K, R, H, G, and F.
Aspect 321. The IL-2R.alpha. ligand of any one of aspects 302 to
320, wherein X.sup.3 is C.
Aspect 322. The IL-2R.alpha. ligand of any one of aspects 302 to
321, wherein X.sup.4 is selected from F, I, L, M, V, W, and Y.
Aspect 323. The IL-2R.alpha. ligand of any one of aspects 302 to
321, wherein X.sup.4 is selected from H, K, and R.
Aspect 324. The IL-2R.alpha. ligand of any one of aspects 302 to
323, wherein X.sup.5 is selected from Y, L, E, D, S, I, Y, D, and
R.
Aspect 325. The IL-2R.alpha. ligand of any one of aspects 302 to
324, wherein X.sup.6 is selected from Y, L, E, D, S, and R.
Aspect 326. The IL-2R.alpha. ligand of any one of aspects 302 to
324, wherein X.sup.6 is selected from D and E.
Aspect 327. The IL-2R.alpha. ligand of any one of aspects 302 to
326, wherein X.sup.7 is selected from G, E, K, T, P, W, L, Y, G, S,
and R.
Aspect 328. The IL-2R.alpha. ligand of any one of aspects 302 to
327, wherein X.sup.8 is selected from I, A, Q, R, S R, L, N, P, A,
I, R, D, and W.
Aspect 329. The IL-2R.alpha. ligand of any one of aspects 302 to
328, wherein X.sup.9 is selected from W, G, S, D, R, L, F, P, A,
and T.
Aspect 330. The IL-2R.alpha. ligand of any one of aspects 302 to
329, wherein X.sup.10 is selected from G, T, E, W, Q, R, and Y.
Aspect 331. The IL-2R.alpha. ligand of any one of aspects 302 to
329, wherein X.sup.10 is G.
Aspect 332. The IL-2R.alpha. ligand of any one of aspects 302 to
331, wherein X.sup.11 is selected from H, P, I, T, H, A, S, F, and
Y.
Aspect 333. The IL-2R.alpha. ligand of any one of aspects 302 to
332, wherein X.sup.12 is C.
Aspect 334. The IL-2R.alpha. ligand of any one of aspects 302 to
333, wherein X.sup.13 is selected from F, I, L, M, V, W, and Y.
Aspect 335. The IL-2R.alpha. ligand of any one of aspects 302 to
334, wherein X.sup.14 is F.
Aspect 336. The IL-2R.alpha. ligand of aspect 302, wherein X.sup.2
is R, X.sup.3 is C, X.sup.6, is D, X.sup.10 is G, X.sup.12 is C,
and X.sup.14 is F.
Aspect 337. The IL-2R.alpha. ligand of aspect 302, wherein,
X.sup.1 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.2 is R;
X.sup.3 is C;
X.sup.4 is selected from F, H, I, K, L, M, R, V, W, and Y;
X.sup.5 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.6 is D;
X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.8 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.9 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.10 is G;
X.sup.11 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.12 is C;
X.sup.13 is selected from F, I, L, M, V, W, and Y; and
X.sup.14 is F.
Aspect 338. The IL-2R.alpha. ligand of aspect 302, wherein the
IL-2R.alpha. ligand comprises an amino acid sequence selected from
any one of SEQ ID NO: 72 to SEQ ID NO: 86:
TABLE-US-00034 SEQ ID NO: 72 R S C N R Y G I W G H C D T SEQ ID NO:
73 I K C R V L E A G T P C V F SEQ ID NO: 74 I R C R Y E K Q S G I
C L F SEQ ID NO: 75 L R C R L D T R D G T C R F SEQ ID NO: 76 M R C
I L S P S R E H C L F SEQ ID NO: 77 N H C T M D W R L G A C I F SEQ
ID NO: 78 S G C R L S L L D G H C Y F SEQ ID NO: 79 S K C V Y D Y N
F G T C I F SEQ ID NO: 80 S R C V M S L Q L G A C I F SEQ ID NO: 81
T R C T V I G P P W S C R F SEQ ID NO: 82 V F C I G Y G A A Q S C H
S SEQ ID NO: 83 V R C L Y D S I T R T C T F SEQ ID NO: 84 V S C K I
D R R S G S C L F SEQ ID NO: 85 V S C R F R P D L G F C I F SEQ ID
NO: 86 D R C D T R T W G Y Y C W I
Aspect 339. The IL-2R.alpha. ligand of any one of aspects 302 to
338, wherein,
the amino acid sequence independently comprises from 1 to 4
glycines (G) (SEQ ID NO: 1041) on the N-terminus, on the
C-terminus, or on both the N- and C-termini;
the amino acid sequence comprises a truncated amino acid sequence;
or
the amino acid sequence comprises a truncated amino acid sequence,
wherein the truncated amino acid sequence independently comprises
from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on
the C-terminus, or on both the N- and C-termini.
Aspect 340. The IL-2R.alpha. ligand of any one of aspects 338 to
339, wherein from 1 to 5 of the amino acids is independently
substituted with another amino acid.
Aspect 341. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises the amino acid sequence
of Formula (9a) (SEQ ID NO: 87), the amino acid sequence of Formula
(9b) (SEQ ID NO: 88), the amino acid sequence of Formula (9c) (SEQ
ID NO: 89), or the amino acid sequence of Formula (9d) (SEQ ID NO:
90):
--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.sup.11--X.sup.-
12-- (9a)
--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.su-
p.10--X.sup.11--X.sup.12--C--X.sup.14-- (9b)
--X.sup.2--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup-
.10--X.sup.11--X.sup.12--C--X.sup.14--X.sup.15-- (9c)
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12--X.sup.13--X.sup.14--X.sup.15--X.su-
p.16-- (9d)
wherein, X.sup.1 is selected from an amino acid; X.sup.2 is
selected from an amino acid comprising a large hydrophobic side
chain; X.sup.3 is selected from an amino acid comprising a large
hydrophobic side chain or an acidic side chain; X.sup.4 is C;
X.sup.5 is selected from an amino acid comprising a large
hydrophobic side chain or a basic side chain; X.sup.6 is selected
from an amino acid comprising a large hydrophobic side chain;
X.sup.7 is selected from an amino acid; X.sup.8 is selected from an
amino acid comprising a small hydrophobic side chain; X.sup.9 is
selected from an amino acid comprising a small hydrophobic side
chain; X.sup.10 is selected from an amino acid comprising a large
hydrophobic side chain or a basic side chain; X.sup.11 is selected
from an amino acid comprising a basic side chain or an acidic side
chain; X.sup.12 is selected from an amino acid comprising a small
hydrophobic side chain or a polar neutral side chain; X.sup.13 is
C; X.sup.14 is selected from an amino acid; X.sup.15 is selected
from an amino acid; and X.sup.16 is selected from an amino
acid.
Aspect 342. The IL-2R.alpha. ligand of aspect 341, wherein,
X.sup.1 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.2 is selected from F, I, L, M, V, W, and Y;
X.sup.3 is selected from D, E, F, I, L, M, V, W, and Y;
X.sup.4 is C;
X.sup.5 is selected from F, H, I, K, L, M, R, V, W, and Y;
X.sup.6 is selected from F, I, L, M, V, W, and Y;
X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.8 is selected from A, G, P, S, and T;
X.sup.9 is selected from A, G, P, S, and T;
X.sup.10 is selected from F, H, I, K, L, M, R, V, W, and Y;
X.sup.11 is selected from D, E, H, K, and R;
X.sup.12 is selected from A, G, H, N, P, Q, S, T, and Y;
X.sup.13 is C;
X.sup.14 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.15 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y; and
X.sup.16 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y.
Aspect 343. The IL-2R.alpha. ligand of any one of aspects 341 to
342, wherein X.sup.1 is selected from G, E, F, K, P, Q, R, S, and
V.
Aspect 344. The IL-2R.alpha. ligand of any one of aspects 341 to
343, wherein X.sup.2 is selected from S, W, I, F, L, and R.
Aspect 345. The IL-2R.alpha. ligand of any one of aspects 341 to
344, wherein X.sup.3 is selected from R, E, I, V, S, N, F, L, and
M.
Aspect 346. The IL-2R.alpha. ligand of any one of aspects 341 to
345, wherein X.sup.4 is C.
Aspect 347. The IL-2R.alpha. ligand of any one of aspects 341 to
346, wherein X.sup.5 is selected from Y, R, V, T, E, I, and K.
Aspect 348. The IL-2R.alpha. ligand of any one of aspects 341 to
347, wherein X.sup.6 is selected from W, F, Y, L, H, I, T, S, and
V.
Aspect 349. The IL-2R.alpha. ligand of any one of aspects 341 to
348, wherein X.sup.7 is selected from D, L, S, D, V, Y, S, Q, I, R,
M, G, and A.
Aspect 350. The IL-2R.alpha. ligand of any one of aspects 341 to
349, wherein X.sup.8 is P.
Aspect 351. The IL-2R.alpha. ligand of any one of aspects 341 to
350, wherein X.sup.9 is G.
Aspect 352. The IL-2R.alpha. ligand of any one of aspects 341 to
351, wherein X.sup.10 is selected from R, S, T, N, R, V, L, H, W,
and Y.
Aspect 353. The IL-2R.alpha. ligand of any one of aspects 341 to
352, wherein X.sup.11 is selected from E, R, H, G, E, K, Q, and
V.
Aspect 354. The IL-2R.alpha. ligand of any one of aspects 341 to
353, wherein X.sup.12 is selected from V, G, S, A, and W.
Aspect 355. The IL-2R.alpha. ligand of any one of aspects 341 to
354, wherein X.sup.13 is C.
Aspect 356. The IL-2R.alpha. ligand of any one of aspects 341 to
355, wherein X.sup.14 is selected from I, S, R, W, H, V, K, T, R,
G, and P.
Aspect 357. The IL-2R.alpha. ligand of any one of aspects 341 to
356, wherein X.sup.15 is selected from F, L, M, S, W, T, A, and
R.
Aspect 358. The IL-2R.alpha. ligand of any one of aspects 341 to
357, wherein X.sup.16 is selected from K, F, V, I, F, M, L, Q, T,
and N.
Aspect 359. The IL-2R.alpha. ligand of any one of aspects 341 to
358, wherein X.sup.1 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 360. The IL-2R.alpha. ligand of any one of aspects 341 to
359, wherein X.sup.2 is selected from F, W, and Y.
Aspect 361. The IL-2R.alpha. ligand of any one of aspects 341 to
360, wherein X.sup.3 is W.
Aspect 362. The IL-2R.alpha. ligand of any one of aspects 341 to
361, wherein X.sup.4 is C.
Aspect 363. The IL-2R.alpha. ligand of any one of aspects 341 to
362, wherein X.sup.5 is selected from F, I, L, M, V, W, and Y.
Aspect 364. The IL-2R.alpha. ligand of any one of aspects 341 to
362, wherein X.sup.5 is selected from D and E.
Aspect 365. The IL-2R.alpha. ligand of any one of aspects 341 to
364, wherein X.sup.6 is selected from F, I, L, M, V, W, and Y.
Aspect 366. The IL-2R.alpha. ligand of any one of aspects 341 to
364, wherein X.sup.6 is selected from F, W, and Y.
Aspect 367. The IL-2R.alpha. ligand of any one of aspects 341 to
366, wherein X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 368. The IL-2R.alpha. ligand of any one of aspects 341 to
367, wherein X.sup.8 is P.
Aspect 369. The IL-2R.alpha. ligand of any one of aspects 341 to
368, wherein X.sup.9 is G.
Aspect 370. The IL-2R.alpha. ligand of any one of aspects 341 to
369, wherein X.sup.10 is selected from F, I, L, M, V, W, and Y.
Aspect 371. The IL-2R.alpha. ligand of any one of aspects 341 to
369, wherein X.sup.10 is selected from F, W, and Y.
Aspect 372. The IL-2R.alpha. ligand of any one of aspects 341 to
371, wherein X.sup.10 is selected from H, K, and R.
Aspect 373. The IL-2R.alpha. ligand of any one of aspects 341 to
372, wherein X.sup.11 is selected from H, K, and R.
Aspect 374. The IL-2R.alpha. ligand of any one of aspects 341 to
372, wherein X.sup.11 is selected from D and E.
Aspect 375. The IL-2R.alpha. ligand of any one of aspects 341 to
374, wherein X.sup.12 is selected from A, G, P, S, and T.
Aspect 376. The IL-2R.alpha. ligand of any one of aspects 341 to
374, wherein X.sup.12 is selected from N, Q, S, T, and Y.
Aspect 377. The IL-2R.alpha. ligand of any one of aspects 341 to
376, wherein X.sup.13 is C.
Aspect 378. The IL-2R.alpha. ligand of any one of aspects 341 to
377, wherein X.sup.14 is selected from A, D, E, F, G, H, I, K, L,
M, N, P, Q, R, S, T, V, W, and Y.
Aspect 379. The IL-2R.alpha. ligand of any one of aspects 341 to
378, wherein X.sup.15 is selected from A, D, E, F, G, H, I, K, L,
M, N, P, Q, R, S, T, V, W, and Y.
Aspect 380. The IL-2R.alpha. ligand of any one of aspects 341 to
379, wherein X.sup.16 is selected from A, D, E, F, G, H, I, K, L,
M, N, P, Q, R, S, T, V, W, and Y.
Aspect 381. The IL-2R.alpha. ligand of any one of aspects 341 to
379, wherein X.sup.16 is selected from F, I, L, M, V, W, and Y.
Aspect 382. The IL-2R.alpha. ligand of any one of aspects 341 to
379, wherein X.sup.16 is selected from F, W, and Y.
Aspect 383. The IL-2R.alpha. ligand of aspect 341, wherein X.sup.2
is W, X.sup.3 is E, X.sup.4 is C, X.sup.5, is R, X.sup.8 is P,
X.sup.9 is G, X.sup.10 is R, X.sup.1 is R, X.sup.12 is G, and
X.sup.11 is C.
Aspect 384. The IL-2R.alpha. ligand of aspect 341, wherein,
X.sup.1 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.2 is W;
X.sup.3 is E;
X.sup.4 is C;
X.sup.5 is R;
X.sup.6 is selected from F, H, I, L, M, V, W, and Y;
X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.8 is P;
X.sup.9 is G
X.sup.10 is R;
X.sup.11 is R;
X.sup.12 is G;
X.sup.13 is C;
X.sup.14 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.15 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y; and
X.sup.16 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y.
Aspect 385. The IL-2R.alpha. ligand of aspect 341, wherein the
IL-2R.alpha. ligand comprises an amino acid sequence selected from
any one of SEQ ID NO: 91 to SEQ ID NO: 104:
TABLE-US-00035 SEQ ID NO: 91 G S R C Y W D P G R E V C I F K SEQ ID
NO: 92 E W E C R F L P G R R G C S L F SEQ ID NO: 93 F W E C V Y S
P G S R G C R M V SEQ ID NO: 94 G F R C T Y D P G T H S C W S I SEQ
ID NO: 95 K W I C R L V P G N G A C H S F SEQ ID NO: 96 P W V C E H
Y P G R R G C V L M SEQ ID NO: 97 Q W S C V F S P G V R G C K L V
SEQ ID NO: 98 R F I C R I Q P G R E G C W S L SEQ ID NO: 99 R W E C
I Y I P G R K G C T L Q SEQ ID NO: 100 S L N C K T R P G L R W C T
W T SEQ ID NO: 101 S W E C V Y M P G H Q G C R L F SEQ ID NO: 102 V
R F C R S G P G W V S C G T Q SEQ ID NO: 103 V R L C R V G P G Y E
S C P A N SEQ ID NO: 104 V R M C Y V A P G Y V S C P R M
Aspect 386. The IL-2R.alpha. ligand of any one of aspects 341 to
385, wherein,
the amino acid sequence independently comprises from 1 to 4
glycines (G) (SEQ ID NO: 1041) on the N-terminus, on the
C-terminus, or on both the N- and C-termini;
the amino acid sequence comprises a truncated amino acid sequence;
or
the amino acid sequence comprises a truncated amino acid sequence,
wherein the truncated amino acid sequence independently comprises
from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on
the C-terminus, or on both the N- and C-termini.
Aspect 387. The IL-2R.alpha. ligand of any one of aspects 385 to
386, wherein from 1 to 5 of the amino acids is independently
substituted with another amino acid.
Aspect 388. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises the amino acid sequence
of Formula (10a) (SEQ ID NO: 105), the amino acid sequence of
Formula (10b) (SEQ ID NO: 106), the amino acid sequence of Formula
(10c) (SEQ ID NO: 107), or the amino acid sequence of Formula (10d)
(SEQ ID NO: 108):
--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.sup.11--X.sup.-
12-- (10a)
--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.su-
p.11--X.sup.12--C--X.sup.14-- (10b)
--X.sup.2--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup-
.10--X.sup.11--X.sup.12--C--X.sup.14--X.sup.15-- (10c)
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12--X.sup.13--X.sup.14--X.sup.15--X.su-
p.16-- (10d)
wherein, X.sup.1 is selected from an amino acid comprising an
acidic side chain; X.sup.2 is selected from an amino acid
comprising a large hydrophobic side chain; X.sup.3 is selected from
an amino acid comprising an acidic side chain; X.sup.4 is C;
X.sup.5 is selected from an amino acid comprising a large
hydrophobic side chain; X.sup.6 is selected from an amino acid
comprising a large hydrophobic side chain; X.sup.7 is selected from
an amino acid comprising a large hydrophobic side chain; X.sup.8 is
selected from an amino acid comprising a small hydrophobic side
chain; X.sup.9 is selected from an amino acid comprising a small
hydrophobic side chain; X.sup.10 is selected from an amino acid
comprising a basic side chain; X.sup.11 is selected from an amino
acid comprising a basic side chain; X.sup.12 is selected from an
amino acid comprising a small hydrophobic side chain; X.sup.13 is
C; X.sup.14 is selected from an amino acid comprising a small
hydrophobic side chain or a polar neutral side chain; X.sup.15 is
selected from an amino acid comprising a large hydrophobic side
chain; and X.sup.16 is selected from an amino acid comprising a
large hydrophobic side chain.
Aspect 389. The IL-2R.alpha. ligand of aspect 388, wherein,
X.sup.1 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.2 is selected from F, I, L, M, V, W, and Y;
X.sup.3 is selected from D and E;
X.sup.4 is C;
X.sup.5 is selected from F, I, L, M, V, W, and Y;
X.sup.6 is selected from F, I, L, M, V, W, and Y;
X.sup.7 is selected from F, I, L, M, V, W, and Y;
X.sup.8 is selected from A, G, P, S, and T;
X.sup.9 is selected from A, G, P, S, and T;
X.sup.10 is selected from H, K, and R;
X.sup.11 is selected from H, K, and R;
X.sup.12 is selected from A, G, P, S, and T;
X.sup.13 is C;
X.sup.14 is selected from A, G, H, N, P, Q, S, T, and Y;
X.sup.15 is selected from F, I, L, M, V, W, and Y; and
X.sup.16 is selected from F, I, L, M, V, W, and Y.
Aspect 390. The IL-2R.alpha. ligand of any one of aspects 388 to
389, wherein X.sup.1 is selected from N, D, E, A, V, and T.
Aspect 391. The IL-2R.alpha. ligand of any one of aspects 388 to
390, wherein X.sup.2 is selected from W and Y.
Aspect 392. The IL-2R.alpha. ligand of any one of aspects 388 to
391, wherein X.sup.3 is selected from E, H, and D.
Aspect 393. The IL-2R.alpha. ligand of any one of aspects 388 to
392, wherein X.sup.4 is C.
Aspect 394. The IL-2R.alpha. ligand of any one of aspects 388 to
393, wherein X.sup.5 is selected from I, 1, W, and V.
Aspect 395. The IL-2R.alpha. ligand of any one of aspects 388 to
394, wherein X.sup.6 is selected from F and I.
Aspect 396. The IL-2R.alpha. ligand of any one of aspects 388 to
395, wherein X.sup.7 is selected from S, L, and M.
Aspect 397. The IL-2R.alpha. ligand of any one of aspects 388 to
396, wherein X.sup.8 is P.
Aspect 398. The IL-2R.alpha. ligand of any one of aspects 388 to
397, wherein X.sup.9 is G.
Aspect 399. The IL-2R.alpha. ligand of any one of aspects 388 to
398, wherein X.sup.10 is selected from R and H.
Aspect 400. The IL-2R.alpha. ligand of any one of aspects 388 to
399, wherein X.sup.11 is selected from R and K.
Aspect 401. The IL-2R.alpha. ligand of any one of aspects 388 to
400, wherein X.sup.12 is G.
Aspect 402. The IL-2R.alpha. ligand of any one of aspects 388 to
401, wherein X.sup.13 is C.
Aspect 403. The IL-2R.alpha. ligand of any one of aspects 388 to
402, wherein X.sup.14 is selected from S, L, T, and F.
Aspect 404. The IL-2R.alpha. ligand of any one of aspects 388 to
403, wherein X.sup.15 is selected from L and G.
Aspect 405. The IL-2R.alpha. ligand of any one of aspects 388 to
404, wherein X.sup.16 is selected from F, M, T, and I.
Aspect 406. The IL-2R.alpha. ligand of any one of aspects 388 to
405, wherein X.sup.1 is selected from D and E.
Aspect 407. The IL-2R.alpha. ligand of any one of aspects 388 to
406, wherein X.sup.2 is W.
Aspect 408. The IL-2R.alpha. ligand of any one of aspects 388 to
407, wherein X.sup.3 is selected from D and E.
Aspect 409. The IL-2R.alpha. ligand of any one of aspects 388 to
408, wherein X.sup.4 is C.
Aspect 410. The IL-2R.alpha. ligand of any one of aspects 388 to
409, wherein X.sup.5 is selected from F, I, L, M, V, W, and Y.
Aspect 411. The IL-2R.alpha. ligand of any one of aspects 388 to
409, wherein X.sup.5 is selected from I and L.
Aspect 412. The IL-2R.alpha. ligand of any one of aspects 388 to
411, wherein X.sup.6 is F.
Aspect 413. The IL-2R.alpha. ligand of any one of aspects 388 to
412, wherein X.sup.7 is selected from L and M.
Aspect 414. The IL-2R.alpha. ligand of any one of aspects 388 to
413, wherein X.sup.8 is P.
Aspect 415. The IL-2R.alpha. ligand of any one of aspects 388 to
414, wherein X.sup.9 is G.
Aspect 416. The IL-2R.alpha. ligand of any one of aspects 388 to
415, wherein X.sup.10 is selected from H and R.
Aspect 417. The IL-2R.alpha. ligand of any one of aspects 388 to
416, wherein X.sup.11 is selected from K and R.
Aspect 418. The IL-2R.alpha. ligand of any one of aspects 388 to
417, wherein X.sup.12 is G.
Aspect 419. The IL-2R.alpha. ligand of any one of aspects 388 to
418, wherein X.sup.13 is C.
Aspect 420. The IL-2R.alpha. ligand of any one of aspects 388 to
419, wherein X.sup.14 is selected from S and T.
Aspect 421. The IL-2R.alpha. ligand of any one of aspects 388 to
420, wherein X.sup.15 is L.
Aspect 422. The IL-2R.alpha. ligand of any one of aspects 388 to
421, wherein X.sup.16 is selected from F and M.
Aspect 423. The IL-2R.alpha. ligand of aspect 388, wherein,
X.sup.1 is D;
X.sup.2 is W;
X.sup.3 is E;
X.sup.4 is C;
X.sup.5 is L;
X.sup.6 is F;
X.sup.7 is L;
X.sup.8 is P;
X.sup.9 is G;
X.sup.10 is selected from H and R;
X.sup.11 is selected from K and R;
X.sup.12 is G;
X.sup.13 is C;
X.sup.14 is T;
X.sup.15 is L; and
X.sup.16 is F.
Aspect 424. The IL-2R.alpha. ligand of aspect 388, wherein the
IL-2R.alpha. ligand comprises an amino acid sequence selected from
any one of SEQ ID NO: 109 to SEQ ID NO: 121:
TABLE-US-00036 SEQ ID NO: 109 N W E C I F S P G R R G C S L T SEQ
ID NO: 110 D W E C L F L P G R R G C L L F SEQ ID NO: 111 E W E C L
F M P G R R G C L L M SEQ ID NO: 112 A W E C L F L P G H R G C S L
F SEQ ID NO: 113 E W E C L F L P G R K G C T L F SEQ ID NO: 114 D W
E C I F L P G R R G C T L F SEQ ID NO: 115 V Y E C L F M P G R K G
C F G M SEQ ID NO: 116 E W E C W F L P G R R G C T L I SEQ ID NO:
117 D W H C L F L P G H R G C T L F SEQ ID NO: 118 D W E C L F L P
G R R G C T L F SEQ ID NO: 119 Y W E C V F M P G H R G C S L I SEQ
ID NO: 120 T W D C L F L P G R R G C T L M SEQ ID NO: 121 N W E C I
F S P G R R G C S L T
Aspect 425. The IL-2R.alpha. ligand of any one of aspects 388 to
424, wherein,
the amino acid sequence independently comprises from 1 to 4
glycines (G) (SEQ ID NO: 1041) on the N-terminus, on the
C-terminus, or on both the N- and C-termini;
the amino acid sequence comprises a truncated amino acid sequence;
or
the amino acid sequence comprises a truncated amino acid sequence,
wherein the truncated amino acid sequence independently comprises
from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on
the C-terminus, or on both the N- and C-termini.
Aspect 426. The IL-2R.alpha. ligand of any one of aspects 424 to
425, wherein from 1 to 5 of the amino acids is independently
substituted with another amino acid.
Aspect 427. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises the amino acid sequence
of Formula (11a) (SEQ ID NO: 122), the amino acid sequence of
Formula (11b) (SEQ ID NO: 123), the amino acid sequence of Formula
(11c) (SEQ ID NO: 124), or the amino acid sequence of Formula (11d)
(SEQ ID NO: 125):
--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.sup.11--X.sup.-
12-- (11a)
--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.su-
p.11--X.sup.12--C--X.sup.14-- (11b)
--X.sup.2--X.sup.3--C--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup-
.10--X.sup.11--X.sup.12--C--X.sup.14--X.sup.15-- (11c)
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12--X.sup.13--X.sup.14--X.sup.15--X.su-
p.16-- (11d)
wherein, X.sup.1 is selected from an amino acid; X.sup.2 is
selected from an amino acid; X.sup.3 is selected from an amino
acid; X.sup.4 is C; X.sup.5 is selected from an amino acid
comprising an acidic side chain; X.sup.6 is selected from an amino
acid X.sup.7 is selected from an amino acid comprising an acidic
side chain or an aromatic side chain; X.sup.8 is selected from an
amino acid comprising a small hydrophobic side chain; X.sup.9 is
selected from an amino acid comprising a small hydrophobic side
chain; X.sup.10 is selected from an amino acid comprising an
aromatic chain; X.sup.11 is selected from an amino acid; X.sup.12
is selected from an amino acid; X.sup.13 is C; X.sup.14 is selected
from an amino acid; X.sup.15 is selected from an amino acid
comprising a large hydrophobic side chain; and X.sup.16 is selected
from an amino acid comprising a large hydrophobic side chain.
Aspect 428. The IL-2R.alpha. ligand of aspect 427, wherein,
X.sup.1 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.2 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.3 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.4 is C;
X.sup.5 is selected from D and E;
X.sup.6 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.7 is selected from D, E, F, H, W, and Y;
X.sup.8 is selected from A, G, P, S, and T;
X.sup.9 is selected from A, G, P, S, and T;
X.sup.10 is selected from F, H, W, and Y;
X.sup.11 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y
X.sup.12 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.13 is C;
X.sup.14 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.15 is selected from F, I, L, M, V, W, and Y; and
X.sup.16 is selected from F, I, L, M, V, W, and Y.
Aspect 429. The IL-2R.alpha. ligand of any one of aspects 427 to
428, wherein X.sup.1 is selected from A, E, F, G, K, R, T, Y, and
W.
Aspect 430. The IL-2R.alpha. ligand of any one of aspects 427 to
429, wherein X.sup.2 is selected from G, T, K, Q, S, L, Q, R, and
A.
Aspect 431. The IL-2R.alpha. ligand of any one of aspects 427 to
430, wherein X.sup.3 is selected from F, Y, W, and H.
Aspect 432. The IL-2R.alpha. ligand of any one of aspects 427 to
430, wherein X.sup.3 is selected from G, W, P, L, R, F, M, V, S,
and P.
Aspect 433. The IL-2R.alpha. ligand of any one of aspects 427 to
432, wherein X.sup.4 is C.
Aspect 434. The IL-2R.alpha. ligand of any one of aspects 427 to
433, wherein X.sup.5 is selected from K, D, Y, T, Y, Q, F, L, and
S.
Aspect 435. The IL-2R.alpha. ligand of any one of aspects 427 to
434, wherein X.sup.6 is selected from L, D, F, Y, W, N, D, M, V, D,
L, and Y.
Aspect 436. The IL-2R.alpha. ligand of any one of aspects 427 to
435, wherein X.sup.7 is selected from N, H, F, D, N, S, L, and
Y.
Aspect 437. The IL-2R.alpha. ligand of any one of aspects 427 to
436, wherein X.sup.8 is P.
Aspect 438. The IL-2R.alpha. ligand of any one of aspects 427 to
437, wherein X.sup.9 is G.
Aspect 439. The IL-2R.alpha. ligand of any one of aspects 427 to
438, wherein X.sup.10 is selected from T, H, L, S, Q, R, N, Y, W,
V, S, and H.
Aspect 440. The IL-2R.alpha. ligand of any one of aspects 427 to
439, wherein X.sup.11 is selected from Q, W, P, D, E, S, P, E, H,
G, R, and G.
Aspect 441. The IL-2R.alpha. ligand of any one of aspects 427 to
440, wherein X.sup.12 is selected from V, S, R, I, A, D, S, E, Y,
and G.
Aspect 442. The IL-2R.alpha. ligand of any one of aspects 427 to
441, wherein X.sup.13 is C.
Aspect 443. The IL-2R.alpha. ligand of any one of aspects 427 to
442, wherein X.sup.14 is selected from S, E, T, V, I, D, Q, W, P,
I, and Y.
Aspect 444. The IL-2R.alpha. ligand of any one of aspects 427 to
443, wherein X.sup.15 is selected from F, M, W, I, V, T, N, L, and
S.
Aspect 445. The IL-2R.alpha. ligand of any one of aspects 427 to
444, wherein X.sup.16 is selected from Y, V, I, L, S, K, E, and
R.
Aspect 446. The IL-2R.alpha. ligand of any one of aspects 427 to
445, wherein X.sup.4 is C.
Aspect 447. The IL-2R.alpha. ligand of any one of aspects 427 to
446, wherein X.sup.5 is D.
Aspect 448. The IL-2R.alpha. ligand of any one of aspects 427 to
447, wherein X.sup.7 is selected from D and H.
Aspect 449. The IL-2R.alpha. ligand of any one of aspects 427 to
448, wherein X.sup.8 is P.
Aspect 450. The IL-2R.alpha. ligand of any one of aspects 427 to
449, wherein X.sup.9 is G.
Aspect 451. The IL-2R.alpha. ligand of any one of aspects 427 to
450, wherein X.sup.10 is selected from F, H, W, and Y.
Aspect 452. The IL-2R.alpha. ligand of any one of aspects 427 to
451, wherein X.sup.13 is C.
Aspect 453. The IL-2R.alpha. ligand of any one of aspects 427 to
452, wherein X.sup.15 is selected from F, M, I, W, V, and L.
Aspect 454. The IL-2R.alpha. ligand of any one of aspects 427 to
453, wherein X.sup.16 is selected from Y, V, I, and L.
Aspect 455. The IL-2R.alpha. ligand of aspect 427, wherein,
X.sup.1 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.2 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.3 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.4 is C;
X.sup.5 is selected from D and E;
X.sup.6 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.7 is selected from D, E, H, F, W, and Y;
X.sup.8 is P;
X.sup.9 is G;
X.sup.10 is selected from H, F, W, and Y;
X.sup.11 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.12 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.13 is C;
X.sup.14 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.15 is selected from F, I, L, M, V, W, and Y; and
X.sup.16 is selected from F, I, L, M, V, W, and Y.
Aspect 456. The IL-2R.alpha. ligand of aspect 427, wherein the
IL-2R.alpha. ligand comprises an amino acid sequence selected from
any one of SEQ ID NO: 126 to SEQ ID NO: 140:
TABLE-US-00037 SEQ ID NO: 126 A G W C K L N P G T Q V C S F Y SEQ
ID NO: 127 E T P C D L H P G H W S C S M V SEQ ID NO: 128 F F L C D
D F P G L P R C E W I SEQ ID NO: 129 G L R C Y F D P G S Q I C T F
L SEQ ID NO: 130 G Q R C T Y D P G Q D A C V F S SEQ ID NO: 131 G S
R C Y W D P G R E V C I F K SEQ ID NO: 132 K L W C Q N N P G N S I
C D M Y SEQ ID NO: 133 K S W C F D H P G Y P I C Q F Y SEQ ID NO:
134 R L F C L M N P G P P D C W I Y SEQ ID NO: 135 R Q F C L V S P
G Y E D C W F V SEQ ID NO: 136 T R M C F D D P G W H S C P V V SEQ
ID NO: 137 T R W C S L H P G V G E C V T L SEQ ID NO: 138 T T V C D
Y H P G S R Y C I N E SEQ ID NO: 139 Y A S C T Y L P G H R G C T L
V SEQ ID NO: 140 W L P C D D Y P G H G Y C Y S R
Aspect 457. The IL-2R.alpha. ligand of any one of aspects 427 to
456, wherein,
the amino acid sequence independently comprises from 1 to 4
glycines (G) (SEQ ID NO: 1041) on the N-terminus, on the
C-terminus, or on both the N- and C-termini;
the amino acid sequence comprises a truncated amino acid sequence;
or
the amino acid sequence comprises a truncated amino acid sequence,
wherein the truncated amino acid sequence independently comprises
from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on
the C-terminus, or on both the N- and C-termini.
Aspect 458. The IL-2R.alpha. ligand of any one of aspects 456 to
457, wherein from 1 to 5 of the amino acids is independently
substituted with another amino acid.
Aspect 459. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises the amino acid sequence
of Formula (12a) (SEQ ID NO: 141), the amino acid sequence of
Formula (12b) (SEQ ID NO: 142), or the amino acid sequence of
Formula (12c) (SEQ ID NO: 143):
--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.sup.1-
1--X.sup.12-- (12a)
--X.sup.2--C--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup-
.10--X.sup.11--X.sup.12--C--X.sup.14-- (12b)
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12--X.sup.13--X.sup.14--X.sup.15--X.su-
p.16-- (12c)
wherein, X.sup.1 is selected from an amino acid; X.sup.2 is
selected from an amino acid; X.sup.3 is C; X.sup.4 is selected from
an amino acid; X.sup.5 is selected from an amino acid comprising a
large hydrophobic side chain; X.sup.6 is selected from an amino
acid; X.sup.7 is selected from an amino acid; X.sup.8 is selected
from an amino acid; X.sup.9 is selected from an amino acid
comprising an acidic side chain, a small hydrophobic side chain, or
a polar neutral side chain; X.sup.10 is selected from an amino
acid; X.sup.11 is selected from an amino acid comprising a large
hydrophobic side chain; X.sup.12 is selected from an amino acid
comprising a large hydrophobic side chain; X.sup.13 is C; X.sup.14
is selected from an amino acid comprising a large hydrophobic side
chain; and X.sup.15 is selected from an amino acid comprising a
large hydrophobic side chain; X.sup.16 is selected from an amino
acid.
Aspect 471. The IL-2R.alpha. ligand of aspect 459, wherein,
X.sup.1 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.2 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.3 is C;
X.sup.4 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.5 is selected from F, I, L, M, V, W, and Y;
X.sup.6 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.8 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.9 is selected from A, D, E, G, H, N, P, Q, S, T, and Y;
X.sup.10 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.11 is selected from F, I, L, M, V, W, and Y;
X.sup.12 is selected from F, I, L, M, V, W, and Y;
X.sup.13 is C;
X.sup.14 is selected from F, I, L, M, V, W, and Y; and
X.sup.15 is selected from F, I, L, M, V, W, and Y.
Aspect 461. The IL-2R.alpha. ligand of any one of aspects 459 to
460, wherein X.sup.1 is selected from S, N, Q, R, and G.
Aspect 462. The IL-2R.alpha. ligand of any one of aspects 459 to
461, wherein X.sup.2 is selected from A, H, R, and G.
Aspect 463. The IL-2R.alpha. ligand of any one of aspects 459 to
462, wherein X.sup.3 is C.
Aspect 464. The IL-2R.alpha. ligand of any one of aspects 459 to
463, wherein X.sup.4 is selected from Q, T, N, M, and S.
Aspect 465. The IL-2R.alpha. ligand of any one of aspects 459 to
464, wherein X.sup.5 is selected from L and R.
Aspect 466. The IL-2R.alpha. ligand of any one of aspects 459 to
465, wherein X.sup.6 is selected from K, S, R, and V.
Aspect 467. The IL-2R.alpha. ligand of any one of aspects 459 to
466, wherein X.sup.7 is selected from W, K, and L.
Aspect 468. The IL-2R.alpha. ligand of any one of aspects 459 to
467, wherein X.sup.8 is selected from D, T, L, Q, and A.
Aspect 469. The IL-2R.alpha. ligand of any one of aspects 459 to
468, wherein X.sup.9 is selected from E, Y, D, and P.
Aspect 470. The IL-2R.alpha. ligand of any one of aspects 459 to
469, wherein X.sup.10 is selected from G, P, A, E, and S.
Aspect 471. The IL-2R.alpha. ligand of any one of aspects 459 to
470, wherein X.sup.11 is selected from W and L.
Aspect 472. The IL-2R.alpha. ligand of any one of aspects 459 to
471, wherein X.sup.12 is selected from T, V, I, and A.
Aspect 473. The IL-2R.alpha. ligand of any one of aspects 459 to
472, wherein X.sup.13 is C.
Aspect 474. The IL-2R.alpha. ligand of any one of aspects 459 to
473, wherein X.sup.14 is selected from L, V, Q, and I.
Aspect 475. The IL-2R.alpha. ligand of any one of aspects 459 to
474, wherein X.sup.15 is selected from F and A.
Aspect 476. The IL-2R.alpha. ligand of any one of aspects 459 to
475, wherein X.sup.1 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 477. The IL-2R.alpha. ligand of any one of aspects 459 to
476, wherein X.sup.2 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 478. The IL-2R.alpha. ligand of any one of aspects 459 to
477, wherein X.sup.3 is C.
Aspect 479. The IL-2R.alpha. ligand of any one of aspects 459 to
478, wherein X.sup.4 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 480. The IL-2R.alpha. ligand of any one of aspects 459 to
479, wherein X.sup.5 is L.
Aspect 481. The IL-2R.alpha. ligand of any one of aspects 459 to
480, wherein X.sup.6 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 482. The IL-2R.alpha. ligand of any one of aspects 459 to
481, wherein X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 483. The IL-2R.alpha. ligand of any one of aspects 459 to
482, wherein X.sup.8 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 484. The IL-2R.alpha. ligand of any one of aspects 459 to
483, wherein X.sup.9 is selected from D and E.
Aspect 485. The IL-2R.alpha. ligand of any one of aspects 459 to
484, wherein X.sup.10 is selected from A, D, E, F, G, H, I, K, L,
M, N, P, Q, R, S, T, V, W, and Y.
Aspect 486. The IL-2R.alpha. ligand of any one of aspects 459 to
485, wherein X.sup.11 is selected from F, I, L, M, V, W, and Y.
Aspect 487. The IL-2R.alpha. ligand of any one of aspects 459 to
485, wherein X.sup.11 is W.
Aspect 488. The IL-2R.alpha. ligand of any one of aspects 459 to
487, wherein X.sup.12 is selected from F, I, L, M, V, W, and Y.
Aspect 489. The IL-2R.alpha. ligand of any one of aspects 459 to
488, wherein X.sup.13 is C.
Aspect 490. The IL-2R.alpha. ligand of any one of aspects 459 to
489, wherein X.sup.14 is selected from F, I, L, M, V, W, and Y.
Aspect 491. The IL-2R.alpha. ligand of any one of aspects 459 to
490, wherein X.sup.15 is F.
Aspect 492. The IL-2R.alpha. ligand of aspect 459, wherein X.sup.3
is C, X.sup.5 is L, X.sup.9 is D or E, X.sup.11 is W, X.sup.13 is
C, and X.sup.15 is F.
Aspect 493. The IL-2R.alpha. ligand of aspect 459, wherein,
X.sup.1 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.2 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.3 is C;
X.sup.4 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.5 is L;
X.sup.6 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.8 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.9 is selected from D and E;
X.sup.10 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y:
X.sup.11 is selected from F, I, L, M, V, W, and Y;
X.sup.12 is selected from F, I, L, M, V, W, and Y;
X.sup.13 is C;
X.sup.14 is selected from F, I, L, M, V, W, and Y; and
X.sup.15 is F.
Aspect 494. The IL-2R.alpha. ligand of aspect 459, wherein X.sup.3
is C, X.sup.5 is L, X.sup.11 is W, X.sup.11 is C, and X.sup.1 is
F.
Aspect 495. The IL-2R.alpha. ligand of aspect 459, wherein the
IL-2R.alpha. ligand comprises an amino acid sequence selected from
any one of SEQ ID NO: 144 to SEQ ID NO: 148:
TABLE-US-00038 SEQ ID NO: 144 S A C Q L K W D E G W T C L F SEQ ID
NO: 145 N H C T L S K T Y P W V C V F SEQ ID NO: 146 Q R C N R S L
L D A L I C Q A SEQ ID NO: 147 R G C M L R L Q P E L A C V F SEQ ID
NO: 148 G G C S L V W A D S W V C I F
Aspect 496. The IL-2R.alpha. ligand of any one of aspects 459 to
495, wherein,
the amino acid sequence independently comprises from 1 to 4
glycines (G) (SEQ ID NO: 1041) on the N-terminus, on the
C-terminus, or on both the N- and C-termini;
the amino acid sequence comprises a truncated amino acid sequence;
or
the amino acid sequence comprises a truncated amino acid sequence,
wherein the truncated amino acid sequence independently comprises
from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on
the C-terminus, or on both the N- and C-termini.
Aspect 497. The IL-2R.alpha. ligand of any one of aspects 495 to
496, wherein from 1 to 5 of the amino acids is independently
substituted with another amino acid.
Aspect 498. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises the amino acid sequence
of Formula (13a) (SEQ ID NO: 149), the amino acid sequence of
Formula (13b) (SEQ ID NO: 150), or the amino acid sequence of
Formula (13c) (SEQ ID NO: 151):
--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.sup.1-
1--X.sup.12-- (13a)
--X.sup.2--C--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup-
.10--X.sup.11--X.sup.12--C--X.sup.14-- (13b)
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--
-X.sup.9--X.sup.10--X.sup.11--X.sup.12--X.sup.13--X.sup.14--X.sup.15--
(13c)
wherein, X.sup.1 is selected from an amino acid comprising a small
hydrophobic side chain or a basic side chain; X.sup.2 is selected
from an amino acid comprising a small hydrophobic side chain or a
basic side chain; X.sup.3 is C; X.sup.4 is selected from an amino
acid comprising a small hydrophobic side chain; X.sup.5 is selected
from an amino acid comprising a large hydrophobic side chain;
X.sup.6 is selected from an amino acid comprising a large
hydrophobic side chain; X.sup.7 is selected from an amino acid
comprising a large hydrophobic side chain; X.sup.8 is selected from
an amino acid; X.sup.9 is selected from an amino acid comprising an
acidic side chain; X.sup.10 is selected from an amino acid
comprising a small hydrophobic side chain; X.sup.11 is selected
from an amino acid comprising a large hydrophobic side chain;
X.sup.12 is selected from an amino acid comprising a large
hydrophobic side chain or an acidic side chain; X.sup.13 is C;
X.sup.14 is selected from an amino acid comprising a large
hydrophobic side chain; and X.sup.15 is selected from an amino acid
comprising a large hydrophobic side chain.
Aspect 499. The IL-2R.alpha. ligand of aspect 498, wherein,
X.sup.1 is selected from A, G, H, K, P, R, S, and T;
X.sup.2 is selected from A, G, H, K, P, R, S, and T;
X.sup.3 is C;
X.sup.4 is selected from A, G, P, S, and T;
X.sup.5 is selected from F, I, L, M, V, W, and Y;
X.sup.6 is selected from F, I, L, M, V, W, and Y;
X.sup.7 is selected from F, I, L, M, V, W, and Y;
X.sup.8 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.9 is selected from D and E;
X.sup.10 is selected from A, G, P, S, and T;
X.sup.11 is selected from F, I, L, M, V, W, and Y;
X.sup.12 is selected from D, E, F, I, L, M, V, W, and Y;
X.sup.13 is C;
X.sup.14 is selected from F, I, L, M, V, W, and Y; and
X.sup.15 is selected from F, I, L, M, V, W, and Y.
Aspect 500. The IL-2R.alpha. ligand of any one of aspects 498 to
499, wherein X.sup.1 is selected from S, R, Q, V, A, and G.
Aspect 501. The IL-2R.alpha. ligand of any one of aspects 498 to
500, wherein X.sup.2 is selected from R, G, A, and S.
Aspect 502. The IL-2R.alpha. ligand of any one of aspects 498 to
501, wherein X.sup.3 is C.
Aspect 503. The IL-2R.alpha. ligand of any one of aspects 498 to
502, wherein X.sup.4 is selected from S, T, Q, and H.
Aspect 504. The IL-2R.alpha. ligand of any one of aspects 498 to
503, wherein X.sup.5 is L.
Aspect 505. The IL-2R.alpha. ligand of any one of aspects 498 to
504, wherein X.sup.6 is selected from V, Q, A, and R.
Aspect 506. The IL-2R.alpha. ligand of any one of aspects 498 to
505, wherein X.sup.7 is selected from W and F.
Aspect 507. The IL-2R.alpha. ligand of any one of aspects 498 to
506, wherein X.sup.8 is selected from T, D, S, L, A, E, and Q.
Aspect 508. The IL-2R.alpha. ligand of any one of aspects 498 to
507, wherein X.sup.9 is selected from D, G, and E.
Aspect 509. The IL-2R.alpha. ligand of any one of aspects 498 to
507, wherein X.sup.10 is selected from T, S, R, G, A, S, and N.
Aspect 510. The IL-2R.alpha. ligand of any one of aspects 498 to
508, wherein X.sup.11 is W.
Aspect 511. The IL-2R.alpha. ligand of any one of aspects 498 to
510, wherein X.sup.12 is selected from V and E.
Aspect 512. The IL-2R.alpha. ligand of any one of aspects 498 to
511, wherein X.sup.13 is C.
Aspect 513. The IL-2R.alpha. ligand of any one of aspects 498 to
512, wherein X.sup.14 is selected from V and I.
Aspect 514. The IL-2R.alpha. ligand of any one of aspects 498 to
513, wherein X.sup.15 is F.
Aspect 515. The IL-2R.alpha. ligand of any one of aspects 498 to
514, wherein X.sup.1 is selected from A, G, P, S, and T.
Aspect 516. The IL-2R.alpha. ligand of any one of aspects 498 to
514, wherein X.sup.1 is selected from H, K, and R.
Aspect 517. The IL-2R.alpha. ligand of any one of aspects 498 to
516, wherein X.sup.2 is selected from A, G, P, S, and T.
Aspect 518. The IL-2R.alpha. ligand of any one of aspects 498 to
516, wherein X.sup.2 is selected from H, K, and R.
Aspect 519. The IL-2R.alpha. ligand of any one of aspects 498 to
518, wherein X.sup.2 is selected from R and G.
Aspect 520. The IL-2R.alpha. ligand of any one of aspects 498 to
519, wherein X.sup.3 is C.
Aspect 521. The IL-2R.alpha. ligand of any one of aspects 498 to
520, wherein X.sup.4 is selected from A, G, P, S, and T.
Aspect 522. The IL-2R.alpha. ligand of any one of aspects 498 to
520, wherein X.sup.4 is selected from S and T.
Aspect 523. The IL-2R.alpha. ligand of any one of aspects 498 to
522, wherein X.sup.5 is selected from F, I, L, M, V, W, and Y.
Aspect 524. The IL-2R.alpha. ligand of any one of aspects 498 to
522, wherein X.sup.5 is L.
Aspect 525. The IL-2R.alpha. ligand of any one of aspects 498 to
524, wherein X.sup.6 is selected from F, I, L, M, V, W, and Y.
Aspect 526. The IL-2R.alpha. ligand of any one of aspects 498 to
524, wherein X.sup.6 is V.
Aspect 527. The IL-2R.alpha. ligand of any one of aspects 498 to
526, wherein X.sup.7 is selected from F, I, L, M, V, W, and Y.
Aspect 528. The IL-2R.alpha. ligand of any one of aspects 498 to
526, wherein X.sup.7 is selected from F, W, and Y.
Aspect 529. The IL-2R.alpha. ligand of any one of aspects 498 to
526, wherein X.sup.7 is W.
Aspect 530. The IL-2R.alpha. ligand of any one of aspects 498 to
529, wherein X.sup.8 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 531. The IL-2R.alpha. ligand of any one of aspects 498 to
530, wherein X.sup.8 is selected from A, G, P, S, and T.
Aspect 532. The IL-2R.alpha. ligand of any one of aspects 498 to
530, wherein X.sup.8 is A.
Aspect 533. The IL-2R.alpha. ligand of any one of aspects 498 to
532, wherein X.sup.9 is selected from D and E.
Aspect 534. The IL-2R.alpha. ligand of any one of aspects 498 to
532, wherein X.sup.9 is D.
Aspect 535. The IL-2R.alpha. ligand of any one of aspects 498 to
534, wherein X.sup.10 is selected from A, G, P, S, and T.
Aspect 536. The IL-2R.alpha. ligand of any one of aspects 498 to
534, wherein X.sup.10 is S.
Aspect 537. The IL-2R.alpha. ligand of any one of aspects 498 to
536, wherein X.sup.11 is selected from F, I, L, M, V, W, and Y.
Aspect 538. The IL-2R.alpha. ligand of any one of aspects 498 to
536, wherein X.sup.11 is selected from F, W, and Y.
Aspect 539. The IL-2R.alpha. ligand of any one of aspects 498 to
536, wherein X.sup.11 is W.
Aspect 540. The IL-2R.alpha. ligand of any one of aspects 498 to
539, wherein X.sup.12 is selected from F, I, L, M, V, W, and Y.
Aspect 541. The IL-2R.alpha. ligand of any one of aspects 498 to
540, wherein X.sup.12 is selected from D and E.
Aspect 542. The IL-2R.alpha. ligand of any one of aspects 498 to
540, wherein X.sup.12 is selected from V and E.
Aspect 543. The IL-2R.alpha. ligand of any one of aspects 498 to
540, wherein X.sup.12 is V.
Aspect 544. The IL-2R.alpha. ligand of any one of aspects 498 to
543, wherein X.sup.13 is C.
Aspect 545. The IL-2R.alpha. ligand of any one of aspects 498 to
544, wherein X.sup.14 is selected from F, I, L, M, V, W, and Y.
Aspect 546. The IL-2R.alpha. ligand of any one of aspects 498 to
544, wherein X.sup.14 is I.
Aspect 547. The IL-2R.alpha. ligand of any one of aspects 498 to
546, wherein X.sup.15 is F.
Aspect 548. The IL-2R.alpha. ligand of aspect 498, wherein X.sup.2
is R, X.sup.3 is C, X.sup.5 is S, X.sup.6 is L,
X.sup.7 is V, X.sup.8 is W, X.sup.10 is D, X.sup.11 is S, X.sup.12
is W, X.sup.13 is V, X.sup.14 is C, X.sup.15 is I, and X.sup.16 is
F.
Aspect 549. The IL-2R.alpha. ligand of aspect 498, wherein,
X.sup.1 is selected from A, D, E, G, P, S, and T;
X.sup.2 is selected from G and R;
X.sup.3 is C;
X.sup.4 is selected from S and T;
X.sup.5 is L;
X.sup.6 is V;
X.sup.7 is selected from F and W;
X.sup.8 is selected from A, G, P, S, and T;
X.sup.9 is selected from D and E;
X.sup.10 is S;
X.sup.11 is W;
X.sup.12 is V;
X.sup.13 is C;
X.sup.14 is I; and
X.sup.15 is F.
Aspect 550. The IL-2R.alpha. ligand of aspect 498, wherein the
IL-2R.alpha. ligand comprises an amino acid sequence selected from
any one of SEQ ID NO: 152 to SEQ ID NO: 166:
TABLE-US-00039 SEQ ID NO: 152 S R C S L V W T D T W V C V F SEQ ID
NO: 153 S R C T L V F D D S W V C V F SEQ ID NO: 154 R G C S L V W
S G S W E C I F SEQ ID NO: 155 Q A C Q L V W L D S W V C I F SEQ ID
NO: 156 V G C S L V W T D R W E C I F SEQ ID NO: 157 S G C S L Q W
A D G W V C I F SEQ ID NO: 158 A R C S L V W D E A W V C I F SEQ ID
NO: 159 R G C S L V W A G S W E C I F SEQ ID NO: 160 S R C S L V W
A E N W V C I F SEQ ID NO: 161 R R C T L V F L D S W E C I F SEQ ID
NO: 162 R G C T L A W E D S W V C I F SEQ ID NO: 163 R G C S L R F
A E A W E C I F SEQ ID NO: 164 A S C S L V W Q D S W V C I F SEQ ID
NO: 165 S R C S L V W A D S W V C I F SEQ ID NO: 166 G R C H L V W
S D R W E C I F
Aspect 551. The IL-2R.alpha. ligand of any one of aspects 498 to
550, wherein,
the amino acid sequence independently comprises from 1 to 4
glycines (G) (SEQ ID NO: 1041) on the N-terminus, on the
C-terminus, or on both the N- and C-termini;
the amino acid sequence comprises a truncated amino acid sequence;
or
the amino acid sequence comprises a truncated amino acid sequence,
wherein the truncated amino acid sequence independently comprises
from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on
the C-terminus, or on both the N- and C-termini.
Aspect 552. The IL-2R.alpha. ligand of any one of aspects 550 to
551, wherein from 1 to 5 of the amino acids is independently
substituted with another amino acid.
Aspect 553. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises the amino acid sequence
of Formula (14a) (SEQ ID NO: 167), or the amino acid sequence of
Formula (14b) (SEQ ID NO: 168):
--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10-
--X.sup.11--X.sup.12-- (14a)
--X.sup.1--C--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup-
.9--X.sup.10--X.sup.11--X.sup.12--C--X.sup.14-- (14b)
wherein, X.sup.1 is selected from an amino acid comprising a small
hydrophobic side chain; X.sup.2 is C; X.sup.3 is selected from an
amino acid comprising a small hydrophobic side chain; X.sup.4 is
selected from an amino acid comprising a large hydrophobic side
chain; X.sup.5 is selected from an amino acid; X.sup.6 is selected
from an amino acid comprising a large hydrophobic side chain;
X.sup.7 is selected from an amino acid comprising an acidic side
chain or a polar neutral side chain; X.sup.8 is selected from an
amino acid; X.sup.9 is selected from an amino acid; X.sup.10 is
selected from an amino acid comprising a large hydrophobic side
chain; X.sup.11 is selected from an amino acid comprising a large
hydrophobic side chain; X.sup.12 is selected from an amino acid
comprising a large hydrophobic side chain or an acidic side chain;
X.sup.13 is C; and X.sup.14 is selected from an amino acid
comprising a large hydrophobic side chain.
Aspect 554. The IL-2R.alpha. ligand of aspect 553, wherein,
X.sup.1 is selected from A, G, P, S, and T;
X.sup.2 is C;
X.sup.3 is selected from A, G, P, S, and T;
X.sup.4 is selected from F, I, L, M, V, W, and Y;
X.sup.5 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.6 is selected from F, I, L, M, V, W, and Y;
X.sup.7 is selected from D, E, N, Q, S, T, and Y;
X.sup.8 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.9 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.10 is selected from F, I, L, M, V, W, and Y;
X.sup.11 is selected from F, I, L, M, V, W, and Y;
X.sup.11 is selected from D, E, F, I, L, M, V, W, and Y;
X.sup.13 is C; and
X.sup.14 is selected from F, I, L, M, V, W, and Y.
Aspect 555. The IL-2R.alpha. ligand of any one of aspects 553 to
554, wherein X.sup.1 is selected from G and S.
Aspect 556. The IL-2R.alpha. ligand of any one of aspects 553 to
555, wherein X.sup.2 is C.
Aspect 557. The IL-2R.alpha. ligand of any one of aspects 553 to
556, wherein X.sup.3 is selected from T, S, M, and V.
Aspect 558. The IL-2R.alpha. ligand of any one of aspects 553 to
557, wherein X.sup.4 is selected from L and V.
Aspect 559. The IL-2R.alpha. ligand of any one of aspects 553 to
558, wherein X.sup.5 is selected from K, R, M, S, T, and Q.
Aspect 560. The IL-2R.alpha. ligand of any one of aspects 553 to
559, wherein X.sup.6 is selected from W, R, and F.
Aspect 561. The IL-2R.alpha. ligand of any one of aspects 553 to
560, wherein X.sup.7 is selected from E, D, Q, N, G, and S.
Aspect 562. The IL-2R.alpha. ligand of any one of aspects 553 to
561, wherein X.sup.8 is selected from S, G, D, Q, K, and G.
Aspect 563. The IL-2R.alpha. ligand of any one of aspects 553 to
562, wherein X.sup.9 is selected from P, D, G, F, and V.
Aspect 564. The IL-2R.alpha. ligand of any one of aspects 553 to
563, wherein X.sup.10 is selected from N and W.
Aspect 565. The IL-2R.alpha. ligand of any one of aspects 553 to
564, wherein X.sup.11 is W.
Aspect 566. The IL-2R.alpha. ligand of any one of aspects 553 to
565, wherein X.sup.12 is selected from T, V, H, and E.
Aspect 567. The IL-2R.alpha. ligand of any one of aspects 553 to
566, wherein X.sup.13 is C.
Aspect 568. The IL-2R.alpha. ligand of any one of aspects 553 to
567, wherein X.sup.14 is selected from Y, E, I, and V.
Aspect 569. The IL-2R.alpha. ligand of any one of aspects 553 to
568, wherein X.sup.1 is G.
Aspect 570. The IL-2R.alpha. ligand of any one of aspects 553 to
569, wherein X.sup.2 is C.
Aspect 571. The IL-2R.alpha. ligand of any one of aspects 553 to
570, wherein X.sup.3 is selected from S and T.
Aspect 572. The IL-2R.alpha. ligand of any one of aspects 553 to
570, wherein X.sup.3 is T.
Aspect 573. The IL-2R.alpha. ligand of any one of aspects 553 to
572, wherein X.sup.4 is L.
Aspect 574. The IL-2R.alpha. ligand of any one of aspects 553 to
573, wherein X.sup.5 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 575. The IL-2R.alpha. ligand of any one of aspects 553 to
574, wherein X.sup.6 is W.
Aspect 576. The IL-2R.alpha. ligand of any one of aspects 553 to
575, wherein X.sup.7 is selected from D, E, Q, and N.
Aspect 577. The IL-2R.alpha. ligand of any one of aspects 553 to
576, wherein X.sup.8 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 578. The IL-2R.alpha. ligand of any one of aspects 553 to
577, wherein X.sup.9 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 579. The IL-2R.alpha. ligand of any one of aspects 553 to
578, wherein X.sup.10 is W.
Aspect 580. The IL-2R.alpha. ligand of any one of aspects 553 to
579, wherein X.sup.11 is W.
Aspect 581. The IL-2R.alpha. ligand of any one of aspects 553 to
580, wherein X.sup.12 is selected from F, I, L, M, V, W, and Y.
Aspect 582. The IL-2R.alpha. ligand of any one of aspects 553 to
581, wherein X.sup.12 is selected from D and E.
Aspect 583. The IL-2R.alpha. ligand of any one of aspects 553 to
581, wherein X.sup.12 is selected from E and V.
Aspect 584. The IL-2R.alpha. ligand of any one of aspects 553 to
583, wherein X.sup.13 is C.
Aspect 585. The IL-2R.alpha. ligand of any one of aspects 553 to
584, wherein X.sup.14 is selected from F, I, L, M, V, W, and Y.
Aspect 586. The IL-2R.alpha. ligand of any one of aspects 553 to
584, wherein X.sup.14 is selected from I and V.
Aspect 587. The IL-2R.alpha. ligand of aspect 553, wherein X.sup.1
is G, X.sup.2 is C, X.sup.3 is T, X.sup.4 is L, X.sup.6 is W,
X.sup.10 is W, X.sup.11 is W, and X.sup.11 is C.
Aspect 588. The IL-2R.alpha. ligand of aspect 553, wherein,
X.sup.1 is G;
X.sup.2 is C;
X.sup.3 is selected from T and S;
X.sup.4 is L;
X.sup.5 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.6 is W;
X.sup.7 is selected from D, E, N, Q, S, T, and Y;
X.sup.8 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.9 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.10 is W;
X.sup.11 is W;
X.sup.12 is selected from V and E;
X.sup.13 is C; and
X.sup.14 is selected from F, I, L, M, V, W, and Y.
Aspect 589. The IL-2R.alpha. ligand of aspect 553, wherein the
IL-2R.alpha. ligand comprises an amino acid sequence selected from
any one of SEQ ID NO: 169 to SEQ ID NO: 174:
SEQ ID NO: 169 G C T L K W E S P N W T C Y
SEQ ID NO: 170 S C T V R W D G D W W V C E
SEQ ID NO: 171 G C S L M W Q D G W W V C I
SEQ ID NO: 172 G C T L S W N Q G W W H C V
SEQ ID NO: 173 G C M L T R G K F W W E C I
SEQ ID NO: 174 G C V L Q F S G V W W E C V
Aspect 590. The IL-2R.alpha. ligand of any one of aspects 553 to
589, wherein,
the amino acid sequence independently comprises from 1 to 4
glycines (G) (SEQ ID NO: 1041) on the N-terminus, on the
C-terminus, or on both the N- and C-termini;
the amino acid sequence comprises a truncated amino acid sequence;
or
the amino acid sequence comprises a truncated amino acid sequence,
wherein the truncated amino acid sequence independently comprises
from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on
the C-terminus, or on both the N- and C-termini.
Aspect 591. The IL-2R.alpha. ligand of any one of aspects 589 to
590, wherein from 1 to 5 of the amino acids is independently
substituted with another amino acid.
Aspect 592. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises the amino acid sequence
of Formula (15a) (SEQ ID NO: 175), the amino acid sequence of
Formula (15b) (SEQ ID NO: 176), or the amino acid sequence of
Formula (15c) (SEQ ID NO: 177):
--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.sup.1-
1--X.sup.12--X.sup.13-- (15a)
--X.sup.2--C--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup-
.10--X.sup.11--X.sup.12--X.sup.13--C--X.sup.15-- (15b)
--X.sup.1--X.sup.2--C--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup-
.9--X.sup.10--X.sup.11--X.sup.12--X.sup.13--C--X.sup.15--X.sup.16--
(15c)
wherein, X.sup.1 is selected from an amino acid; X.sup.2 is
selected from an amino acid; X.sup.3 is C; X.sup.4 is selected from
an amino acid comprising a polar/neutral side chain or a basic side
chain; X.sup.5 is selected from an amino acid comprising a large
hydrophobic side chain; X.sup.6 is selected from an amino acid;
X.sup.7 is selected from an amino acid comprising a polar neutral
side chain or a basic side chain; X.sup.8 is P; X.sup.9 is G;
X.sup.10 is selected from an amino acid; X.sup.11 is selected from
an amino acid; X.sup.12 is selected from an amino acid comprising a
large hydrophobic side chain; X.sup.13 is selected from an amino
acid comprising an acidic side chain or a polar/neutral side chain;
X.sup.14 is C; X.sup.15 is selected from an amino acid comprising a
large hydrophobic side chain; and X.sup.16 is selected from an
amino acid comprising a large hydrophobic side chain.
Aspect 593. The IL-2R.alpha. ligand of aspect 592, wherein,
X.sup.1 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.2 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.3 is C;
X.sup.4 is selected from H, K, N, Q, R, S, T, and Y;
X.sup.5 is selected from F, I, L, M, V, W, and Y;
X.sup.6 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.7 is selected from H, K, N, Q, R, S, T, and Y;
X.sup.8 is P;
X.sup.9 is G;
X.sup.10 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.11 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.12 is selected from F, I, L, M, V, W, and Y;
X.sup.13 is selected from D, E, N, Q, S, T, and Y;
X.sup.14 is C;
X.sup.15 is selected from F, I, L, M, V, W, and Y; and
X.sup.16 is selected from F, I, L, M, V, W, and Y.
Aspect 594. The IL-2R.alpha. ligand of any one of aspects 592 to
593, wherein X.sup.1 is selected from Q, A, G, K, L, N, P, Q, S,
and T.
Aspect 595. The IL-2R.alpha. ligand of any one of aspects 592 to
594, wherein X.sup.2 is selected from R, G, K, T, P, A, S, and
H.
Aspect 596. The IL-2R.alpha. ligand of any one of aspects 592 to
595, wherein X.sup.3 is C.
Aspect 597. The IL-2R.alpha. ligand of any one of aspects 592 to
596, wherein X.sup.4 is selected from Q, M, S, R, T, I, K, R, H,
and L.
Aspect 598. The IL-2R.alpha. ligand of any one of aspects 592 to
597, wherein X.sup.5 is selected from L, P, M, and V.
Aspect 599. The IL-2R.alpha. ligand of any one of aspects 592 to
598, wherein X.sup.6 is selected from S, L, R, Q, F, W, N, I, and
G.
Aspect 600. The IL-2R.alpha. ligand of any one of aspects 592 to
599, wherein X.sup.7 is selected from K, H, R, W, L, N, F, and
V.
Aspect 601. The IL-2R.alpha. ligand of any one of aspects 592 to
600, wherein X.sup.8 is selected from S, P, T, and L.
Aspect 602. The IL-2R.alpha. ligand of any one of aspects 592 to
601, wherein X.sup.9 is G.
Aspect 603. The IL-2R.alpha. ligand of any one of aspects 592 to
602, wherein X.sup.10 is selected from G, L, S, D, T, E, M, N, F,
H, R, K, and P.
Aspect 604. The IL-2R.alpha. ligand of any one of aspects 592 to
603, wherein X.sup.11 is selected from E, Y, R, G, H, S, I, G, L,
W, F, and V.
Aspect 605. The IL-2R.alpha. ligand of any one of aspects 592 to
604, wherein X.sup.12 is selected from L, W, Y, H, and V.
Aspect 606. The IL-2R.alpha. ligand of any one of aspects 592 to
605, wherein X.sup.13 is selected from G, E, V, T, Q, and A.
Aspect 607. The IL-2R.alpha. ligand of any one of aspects 592 to
606, wherein X.sup.14 is C.
Aspect 608. The IL-2R.alpha. ligand of any one of aspects 592 to
607, wherein X.sup.15 is selected from M, I, V, L, W, R, and F.
Aspect 609. The IL-2R.alpha. ligand of any one of aspects 592 to
609, wherein X.sup.16 is selected from F, S, and G.
Aspect 610. The IL-2R.alpha. ligand of any one of aspects 592 to
609, wherein X.sup.1 is selected from S and T.
Aspect 611. The IL-2R.alpha. ligand of any one of aspects 592 to
610, wherein X.sup.2 is selected from S, T, R, and K.
Aspect 612. The IL-2R.alpha. ligand of any one of aspects 592 to
611, wherein X.sup.3 is C.
Aspect 613. The IL-2R.alpha. ligand of any one of aspects 592 to
612, wherein X.sup.4 is selected from N, Q, S, T, and Y.
Aspect 614. The IL-2R.alpha. ligand of any one of aspects 592 to
612, wherein X.sup.4 is T.
Aspect 615. The IL-2R.alpha. ligand of any one of aspects 592 to
614, wherein X.sup.5 is selected from L, M, and V.
Aspect 616. The IL-2R.alpha. ligand of any one of aspects 592 to
614, wherein X.sup.5 is L.
Aspect 617. The IL-2R.alpha. ligand of any one of aspects 592 to
616, wherein X.sup.6 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 618. The IL-2R.alpha. ligand of any one of aspects 592 to
617, wherein X.sup.7 is selected from N, K, H, and R.
Aspect 619. The IL-2R.alpha. ligand of any one of aspects 592 to
617, wherein X.sup.7 is N.
Aspect 620. The IL-2R.alpha. ligand of any one of aspects 592 to
619, wherein X.sup.8 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 621. The IL-2R.alpha. ligand of any one of aspects 592 to
620, wherein X.sup.8 is selected from A, G, P, S, and T.
Aspect 622. The IL-2R.alpha. ligand of any one of aspects 592 to
620, wherein X.sup.8 is P.
Aspect 623. The IL-2R.alpha. ligand of any one of aspects 592 to
622, wherein X.sup.9 is G.
Aspect 624. The IL-2R.alpha. ligand of any one of aspects 592 to
623, wherein X.sup.10 is selected from A, D, E, F, G, H, I, K, L,
M, N, P, Q, R, S, T, V, W, and Y.
Aspect 625. The IL-2R.alpha. ligand of any one of aspects 592 to
624, wherein X.sup.11 is selected from A, D, E, F, G, H, I, K, L,
M, N, P, Q, R, S, T, V, W, and Y.
Aspect 626. The IL-2R.alpha. ligand of any one of aspects 592 to
625, wherein X.sup.11 is selected from A, G, P, S, and T.
Aspect 627. The IL-2R.alpha. ligand of any one of aspects 592 to
625, wherein X.sup.11 is G.
Aspect 628. The IL-2R.alpha. ligand of any one of aspects 592 to
627, wherein X.sup.12 is W.
Aspect 629. The IL-2R.alpha. ligand of any one of aspects 592 to
628, wherein X.sup.13 is selected from N, Q, S, T, and Y.
Aspect 630. The IL-2R.alpha. ligand of any one of aspects 592 to
628, wherein X.sup.13 is selected from D and E.
Aspect 631. The IL-2R.alpha. ligand of any one of aspects 592 to
628, wherein X.sup.13 is selected from E and Q.
Aspect 632. The IL-2R.alpha. ligand of any one of aspects 592 to
628, wherein X.sup.13 is E.
Aspect 633. The IL-2R.alpha. ligand of any one of aspects 592 to
632, wherein X.sup.14 is C.
Aspect 634. The IL-2R.alpha. ligand of any one of aspects 592 to
633, wherein X.sup.15 is selected from F, I, L, M, V, W, and Y.
Aspect 635. The IL-2R.alpha. ligand of any one of aspects 592 to
633, wherein X.sup.15 is selected from M, I, V, L, and F.
Aspect 636. The IL-2R.alpha. ligand of any one of aspects 592 to
633, wherein X.sup.15 is selected from I and V.
Aspect 637. The IL-2R.alpha. ligand of any one of aspects 592 to
636, wherein X.sup.16 is F.
Aspect 638. The IL-2R.alpha. ligand of aspect 592, wherein X.sup.3
is C, X.sup.5 is L, X.sup.8 is P, X.sup.9 is G, X.sup.12 is W,
X.sup.11 is E, X.sup.14 is C, and X.sup.16 is F.
Aspect 639. The IL-2R.alpha. ligand of aspect 592, wherein,
X.sup.1 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.2 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.3 is C;
X.sup.4 is selected from N, Q, S, T, and Y;
X.sup.5 is L;
X.sup.6 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.7 is selected from N, Q, S, T, and Y;
X.sup.8 is P;
X.sup.9 is G;
X.sup.10 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.11 is selected from A, G, P, S, and T;
X.sup.12 is W;
X.sup.13 is selected from E and Q;
X.sup.14 is C;
X.sup.15 is selected from F, I, L, M, V, W, and Y; and
X.sup.16 is F.
Aspect 640. The IL-2R.alpha. ligand of aspect 592, wherein the
IL-2R.alpha. ligand comprises an amino acid sequence selected from
any one of SEQ ID NO: 178 to SEQ ID NO: 195:
TABLE-US-00040 SEQ ID NO: 178 Q R C Q L S W S G G E L G C M F SEQ
ID NO: 179 A G C M L L K P G L Y W E C I F SEQ ID NO: 180 A R C S L
H H T G S R Y E C I F SEQ ID NO: 181 A T C M L R L L G D G W G C V
F SEQ ID NO: 182 G P C R L S N P G T G W E C I F SEQ ID NO: 183 K G
C T L Q N P G S G W V C L F SEQ ID NO: 184 L A C I L S K P G E H W
E C L F SEQ ID NO: 185 N G C T L S F S G M S W T C V Y SEQ ID NO:
186 N S C I L S N P G L G W Q C V F SEQ ID NO: 187 N T C K L F R S
G N I W Q C I F SEQ ID NO: 188 P S C R L W N P G F G W E C I F SEQ
ID NO: 189 Q S C T L Q R L G H L Y Q C W F SEQ ID NO: 190 S A C T P
N W T G R W W E C V F SEQ ID NO: 191 S K C H L I V S G K F H E C V
F SEQ ID NO: 192 S S C T L F N P G T G W T C V F SEQ ID NO: 193 S T
C R M G N P G G V W G C Y F SEQ ID NO: 194 T H C L V Q W P G P V V
A C R S SEQ ID NO: 195 T R C R L L K L G S L W E C F G
Aspect 641. The IL-2R.alpha. ligand of any one of aspects 592 to
640, wherein,
the amino acid sequence independently comprises from 1 to 4
glycines (G) (SEQ ID NO: 1041) on the N-terminus, on the
C-terminus, or on both the N- and C-termini;
the amino acid sequence comprises a truncated amino acid sequence;
or
the amino acid sequence comprises a truncated amino acid sequence,
wherein the truncated amino acid sequence independently comprises
from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on
the C-terminus, or on both the N- and C-termini.
Aspect 642. The IL-2R.alpha. ligand of any one of aspects 640 to
641, wherein from 1 to 5 of the amino acids is independently
substituted with another amino acid.
Aspect 643. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises the amino acid sequence
of Formula (16a) (SEQ ID NO: 196), or the amino acid sequence of
Formula (16b) (SEQ ID NO: 197):
--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10-
--X.sup.11--X.sup.12--X.sup.13-- (16a)
--X.sup.1--C--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup-
.9--X.sup.10--X.sup.11--X.sup.12--X.sup.13--C--X.sup.15-- (16b)
wherein, X.sup.1 is selected from an amino acid; X.sup.2 is C;
X.sup.3 is selected from an amino acid comprising a basic side
chain; X.sup.4 is selected from an amino acid comprising a large
hydrophobic side chain; X.sup.5 is selected from an amino acid
comprising a basic side chain or a polar/neutral side chain;
X.sup.6 is selected from an amino acid comprising a basic side
chain or a polar/neutral side chain; X.sup.7 is selected from an
amino acid; X.sup.8 is selected from an amino acid; X.sup.9 is
selected from an amino acid; X.sup.10 is selected from an amino
acid; X.sup.11 is selected from an amino acid; X.sup.12 is selected
from an amino acid comprising an aromatic side chain or a large
hydrophobic side chain; X.sup.13 is selected from an amino acid
comprising an acidic side chain; X.sup.14 is C; and X.sup.15 is
selected from an amino acid comprising a large hydrophobic side
chain.
Aspect 644. The IL-2R.alpha. ligand of aspect 643, wherein,
X.sup.1 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.2 is selected from C;
X.sup.3 is selected from H, K, and R;
X.sup.4 is selected from F, I, L, M, V, W, and Y;
X.sup.5 is selected from H, K, N, Q, R, S, T, and Y;
X.sup.6 is selected from H, K, N, Q, R, S, T, and Y;
X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.8 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.9 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.10 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.11 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.12 is selected from F, H, I, L, M, V, W, and Y;
X.sup.13 is selected from D and E;
X.sup.14 is C; and
X.sup.15 is selected from F, I, L, M, V, W, and Y.
Aspect 645. The IL-2R.alpha. ligand of any one of aspects 643 to
644, wherein X.sup.1 is selected from A, K, N, R, and T.
Aspect 646. The IL-2R.alpha. ligand of any one of aspects 643 to
645, wherein X.sup.2 is C.
Aspect 647. The IL-2R.alpha. ligand of any one of aspects 643 to
646, wherein X.sup.3 is selected from W, R, and T.
Aspect 648. The IL-2R.alpha. ligand of any one of aspects 643 to
647, wherein X.sup.4 is selected from R, L, and V.
Aspect 649. The IL-2R.alpha. ligand of any one of aspects 643 to
648, wherein X.sup.5 is selected from S, R, Q, K, and H.
Aspect 650. The IL-2R.alpha. ligand of any one of aspects 643 to
649, wherein X.sup.6 is selected from W, Q, H, K, F, and R.
Aspect 651. The IL-2R.alpha. ligand of any one of aspects 643 to
650, wherein X.sup.7 is selected from R, M, L, A, D, S, and I.
Aspect 652. The IL-2R.alpha. ligand of any one of aspects 643 to
651, wherein X.sup.8 is selected from Y, S, P, G, and A.
Aspect 653. The IL-2R.alpha. ligand of any one of aspects 643 to
652, wherein X.sup.9 is selected from P, R, Y, G, Q, P, and L.
Aspect 654. The IL-2R.alpha. ligand of any one of aspects 643 to
653, wherein X.sup.10 is selected from T, G, P, N, T, N, and A.
Aspect 655. The IL-2R.alpha. ligand of any one of aspects 643 to
654, wherein X.sup.11 is selected from R, G, F, T, G, S, and E.
Aspect 656. The IL-2R.alpha. ligand of any one of aspects 643 to
655, wherein X.sup.12 is selected from T and W.
Aspect 657. The IL-2R.alpha. ligand of any one of aspects 643 to
656, wherein X.sup.13 is selected from F, E, and S.
Aspect 658. The IL-2R.alpha. ligand of any one of aspects 643 to
657, wherein X.sup.14 is C.
Aspect 659. The IL-2R.alpha. ligand of any one of aspects 643 to
658, wherein X.sup.15 is selected from S, L, N, I, and V.
Aspect 660. The IL-2R.alpha. ligand of any one of aspects 643 to
659, wherein X.sup.2 is C.
Aspect 661. The IL-2R.alpha. ligand of any one of aspects 643 to
660, wherein X.sup.3 is R.
Aspect 662. The IL-2R.alpha. ligand of any one of aspects 643 to
661, wherein X.sup.4 is selected from L and V.
Aspect 663. The IL-2R.alpha. ligand of any one of aspects 643 to
662, wherein X.sup.5 is selected from R, K, and H.
Aspect 664. The IL-2R.alpha. ligand of any one of aspects 643 to
663, wherein X.sup.6 is selected from R, K, and H.
Aspect 665. The IL-2R.alpha. ligand of any one of aspects 643 to
664, wherein X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 666. The IL-2R.alpha. ligand of any one of aspects 643 to
665, wherein X.sup.8 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 667. The IL-2R.alpha. ligand of any one of aspects 643 to
665, wherein X.sup.8 is G.
Aspect 668. The IL-2R.alpha. ligand of any one of aspects 643 to
667, wherein X.sup.9 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 669. The IL-2R.alpha. ligand of any one of aspects 643 to
668, wherein X.sup.10 is selected from A, D, E, F, G, H, I, K, L,
M, N, P, Q, R, S, T, V, W, and Y.
Aspect 670. The IL-2R.alpha. ligand of any one of aspects 643 to
669, wherein X.sup.11 is selected from A, D, E, F, G, H, I, K, L,
M, N, P, Q, R, S, T, V, W, and Y.
Aspect 671. The IL-2R.alpha. ligand of any one of aspects 643 to
670, wherein X.sup.12 is selected from F, I, L, M, V, W, and Y.
Aspect 672. The IL-2R.alpha. ligand of any one of aspects 643 to
670, wherein X.sup.12 is selected from F, W, and Y.
Aspect 673. The IL-2R.alpha. ligand of any one of aspects 643 to
670, wherein X.sup.12 is W.
Aspect 674. The IL-2R.alpha. ligand of any one of aspects 643 to
673, wherein X.sup.13 is E.
Aspect 675. The IL-2R.alpha. ligand of any one of aspects 643 to
674, wherein X.sup.14 is C.
Aspect 676. The IL-2R.alpha. ligand of any one of aspects 643 to
675, wherein X.sup.15 is selected from F, I, L, M, V, W, and Y.
Aspect 677. The IL-2R.alpha. ligand of any one of aspects 643 to
675, wherein X.sup.15 is selected from L, I, and V.
Aspect 678. The IL-2R.alpha. ligand of aspect 643, wherein X.sup.2
is C, X.sup.3 is R, X.sup.12 is W, X.sup.13 is E, and X.sup.14 is
C.
Aspect 679. The IL-2R.alpha. ligand of aspect 643, wherein,
X.sup.2 is C;
X.sup.3 is R;
X.sup.4 is selected from F, I, L, M, V, W, and Y;
X.sup.5 is selected from N, Q, S, T, and Y;
X.sup.6 is selected from N, Q, S, T, and Y;
X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.8 is selected from A, G, P, S, and T;
X.sup.9 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.10 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.11 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.12 is W;
X.sup.13 is E;
X.sup.14 is C; and
X.sup.15 is selected from F, I, L, M, V, W, and Y.
Aspect 680. The IL-2R.alpha. ligand of aspect 643, wherein the
IL-2R.alpha. ligand comprises an amino acid sequence selected from
any one of SEQ ID NO: 198 to SEQ ID NO: 204:
TABLE-US-00041 SEQ ID NO: 198 A C W R S W R Y P T R T F C S SEQ ID
NO: 199 K C R L R Q M S R G G W E C L SEQ ID NO: 200 N C R V R H L
P Y P F W S C L SEQ ID NO: 201 R C R L Q K A G G N T W E C I SEQ ID
NO: 202 R C T L R F D A Q T G W E C N SEQ ID NO: 203 T C R L K R S
G P N S W E C I SEQ ID NO: 204 T C T V H R I G L A E W E C V
Aspect 681. The IL-2R.alpha. ligand of any one of aspects 643 to
680, wherein,
the amino acid sequence independently comprises from 1 to 4
glycines (G) (SEQ ID NO: 1041) on the N-terminus, on the
C-terminus, or on both the N- and C-termini;
the amino acid sequence comprises a truncated amino acid sequence;
or
the amino acid sequence comprises a truncated amino acid sequence,
wherein the truncated amino acid sequence independently comprises
from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on
the C-terminus, or on both the N- and C-termini.
Aspect 682. The IL-2R.alpha. ligand of any one of aspects 680 to
681, wherein from 1 to 5 of the amino acids is independently
substituted with another amino acid.
Aspect 683. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises the amino acid sequence
of Formula (17a) (SEQ ID NO: 205), the amino acid sequence of
Formula (17b) (SEQ ID NO: 206), or the amino acid sequence of
Formula (17c) (SEQ ID NO: 207):
--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.sup.1-
1--X.sup.12--X.sup.13-- (17a)
--X.sup.2--C--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup-
.10--X.sup.11--X.sup.12--X.sup.13--C--X.sup.15-- (17b)
--X.sup.1--X.sup.2--C--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup-
.9--X.sup.10--X.sup.11--X.sup.12--X.sup.13--CX.sup.15--X.sup.16--
(17c)
wherein, X.sup.1 is selected from an amino acid comprising a large
hydrophobic side chain; X.sup.2 is selected from an amino acid
comprising a basic side chain; X.sup.3 is C; X.sup.4 is selected
from an amino acid comprising a basic side chain; X.sup.5 is
selected from an amino acid comprising a basic side chain or an
aromatic side chain or a large hydrophobic side chain; X.sup.6 is
selected from an amino acid; X.sup.7 is selected from an amino
acid; X.sup.8 is P; X.sup.9 is G; X.sup.10 is selected from an
amino acid; X.sup.11 is selected from an amino acid; X.sup.12 is
selected from an amino acid; X.sup.13 is selected from an amino
acid; X.sup.14 is C; X.sup.15 is selected from an amino acid
comprising a large hydrophobic side chain; and X.sup.16 is selected
from an amino acid comprising a small hydrophobic side chain.
Aspect 684. The IL-2R.alpha. ligand of aspect 683, wherein,
X.sup.1 is selected from F, I, L, M, V, W, and Y;
X.sup.2 is selected from H, K, and R;
X.sup.3 is C;
X.sup.4 is selected from H, K, and R;
X.sup.5 is selected from F, H, I, K, L, M, R, V, W, and Y;
X.sup.6 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.8 is P;
X.sup.9 is G;
X.sup.10 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.11 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.12 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.13 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.14 is C;
X.sup.15 is selected from F, I, L, M, V, W, and Y; and
X.sup.16 is selected from F, I, L, M, V, W, and Y.
Aspect 685. The IL-2R.alpha. ligand of any one of aspects 683 to
684, wherein X.sup.1 is V.
Aspect 686. The IL-2R.alpha. ligand of any one of aspects 683 to
685, wherein X.sup.2 is selected from K, R, T, and Y.
Aspect 687. The IL-2R.alpha. ligand of any one of aspects 683 to
686, wherein X.sup.3 is C.
Aspect 688. The IL-2R.alpha. ligand of any one of aspects 683 to
687, wherein X.sup.4 is selected from K, F, R, and Y.
Aspect 689. The IL-2R.alpha. ligand of any one of aspects 683 to
688, wherein X.sup.5 is selected from L, M, V, and R.
Aspect 690. The IL-2R.alpha. ligand of any one of aspects 683 to
689, wherein X.sup.6 is selected from V, S, A, L, and E.
Aspect 691. The IL-2R.alpha. ligand of any one of aspects 683 to
690, wherein X.sup.7 is selected from M, E, R, Y, V, and K.
Aspect 692. The IL-2R.alpha. ligand of any one of aspects 683 to
691, wherein X.sup.8 is P.
Aspect 693. The IL-2R.alpha. ligand of any one of aspects 683 to
692, wherein X.sup.9 is G.
Aspect 694. The IL-2R.alpha. ligand of any one of aspects 683 to
693, wherein X.sup.10 is selected from S, R, L, Q, V, and G.
Aspect 695. The IL-2R.alpha. ligand of any one of aspects 683 to
694, wherein X.sup.11 is selected from G, V, T, M, and E.
Aspect 696. The IL-2R.alpha. ligand of any one of aspects 683 to
695, wherein X.sup.12 is selected from W, S, W, A, and M.
Aspect 697. The IL-2R.alpha. ligand of any one of aspects 683 to
696, wherein X.sup.13 is selected from A, Y, E, V, and H.
Aspect 698. The IL-2R.alpha. ligand of any one of aspects 683 to
697, wherein X.sup.14 is C.
Aspect 699. The IL-2R.alpha. ligand of any one of aspects 683 to
697, wherein X.sup.14 is selected from H, T, L, V, F, and R.
Aspect 700. The IL-2R.alpha. ligand of any one of aspects 683 to
697, wherein X.sup.14 is selected from F, A, and S.
Aspect 701. The IL-2R.alpha. ligand of any one of aspects 683 to
700, wherein X.sup.1 is V.
Aspect 702. The IL-2R.alpha. ligand of any one of aspects 683 to
701, wherein X.sup.2 is R.
Aspect 703. The IL-2R.alpha. ligand of any one of aspects 683 to
702, wherein X.sup.3 is C.
Aspect 704. The IL-2R.alpha. ligand of any one of aspects 683 to
703, wherein X.sup.4 is R.
Aspect 705. The IL-2R.alpha. ligand of any one of aspects 683 to
704, wherein X.sup.5 is selected from F, I, L, M, V, W, and Y.
Aspect 706. The IL-2R.alpha. ligand of any one of aspects 683 to
704, wherein X.sup.5 is selected from F, W, and Y.
Aspect 707. The IL-2R.alpha. ligand of any one of aspects 683 to
704, wherein X.sup.5 is selected from H, K, and R.
Aspect 708. The IL-2R.alpha. ligand of any one of aspects 683 to
707, wherein X.sup.6 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 709. The IL-2R.alpha. ligand of any one of aspects 683 to
708, wherein X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 710. The IL-2R.alpha. ligand of any one of aspects 683 to
709, wherein X.sup.8 is P.
Aspect 711. The IL-2R.alpha. ligand of any one of aspects 683 to
710, wherein X.sup.9 is G.
Aspect 712. The IL-2R.alpha. ligand of any one of aspects 683 to
711, wherein X.sup.10 is selected from A, D, E, F, G, H, I, K, L,
M, N, P, Q, R, S, T, V, W, and Y.
Aspect 713. The IL-2R.alpha. ligand of any one of aspects 683 to
712, wherein X.sup.11 is selected from A, D, E, F, G, H, I, K, L,
M, N, P, Q, R, S, T, V, W, and Y.
Aspect 714. The IL-2R.alpha. ligand of any one of aspects 683 to
713, wherein X.sup.12 is selected from A, D, E, F, G, H, I, K, L,
M, N, P, Q, R, S, T, V, W, and Y.
Aspect 715. The IL-2R.alpha. ligand of any one of aspects 683 to
714, wherein X.sup.13 is selected from A, D, E, F, G, H, I, K, L,
M, N, P, Q, R, S, T, V, W, and Y.
Aspect 716. The IL-2R.alpha. ligand of any one of aspects 683 to
715, wherein X.sup.14 is C.
Aspect 717. The IL-2R.alpha. ligand of any one of aspects 683 to
716, wherein X.sup.15 is selected from F, I, L, M, V, W, and Y.
Aspect 718. The IL-2R.alpha. ligand of any one of aspects 683 to
717, wherein X.sup.16 is S.
Aspect 719. The IL-2R.alpha. ligand of aspect 683, wherein X.sup.1
is V, X.sup.2, is R, X.sup.3 is C, X.sup.4 is R, X.sup.14 is C, and
X.sup.16 is S.
Aspect 720. The IL-2R.alpha. ligand of aspect 683, wherein,
X.sup.1 is V;
X.sup.2 is R;
X.sup.3 is C;
X.sup.4 is R;
X.sup.5 is selected from H, F, I, K, L, M, R, V, W, and Y;
X.sup.6 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.8 is P;
X.sup.9 is G;
X.sup.10 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.11 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.12 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.13 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.14 is C;
X.sup.15 is selected from F, I, L, M, V, W, and Y; and
X.sup.16 is S.
Aspect 721. The IL-2R.alpha. ligand of aspect 683, wherein the
IL-2R.alpha. ligand comprises an amino acid sequence selected from
any one of SEQ ID NO: 208 to SEQ ID NO: 213:
TABLE-US-00042 SEQ ID NO: 208 V K C K L V N P G S G W A C H F SEQ
ID NO: 209 V R C F M S E P G R V S Y C T A SEQ ID NO: 210 V R C R L
A R P G L T W E C L S SEQ ID NO: 211 V R C R V L Y P G Q M A V C V
S SEQ ID NO: 212 V T C Y R A V P G V E A Y C F S SEQ ID NO: 213 V Y
C R R E K P G G E M H C R S
Aspect 722. The IL-2R.alpha. ligand of any one of aspects 683 to
721, wherein,
the amino acid sequence independently comprises from 1 to 4
glycines (G) (SEQ ID NO: 1041) on the N-terminus, on the
C-terminus, or on both the N- and C-termini;
the amino acid sequence comprises a truncated amino acid sequence;
or
the amino acid sequence comprises a truncated amino acid sequence,
wherein the truncated amino acid sequence independently comprises
from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on
the C-terminus, or on both the N- and C-termini.
Aspect 723. The IL-2R.alpha. ligand of any one of aspects 721 to
722, wherein from 1 to 5 of the amino acids is independently
substituted with another amino acid.
Aspect 724. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises the amino acid sequence
of Formula (18a) (SEQ ID NO: 214), the amino acid sequence of
Formula (18b) (SEQ ID NO: 215), or the amino acid sequence of
Formula (18c) (SEQ ID NO: 216):
--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10--X.sup.1-
1--X.sup.12--X.sup.13-- (18a)
--X.sup.2--C--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup-
.10--X.sup.11--X.sup.12--X.sup.13--C--X.sup.15-- (18b)
--X.sup.1--X.sup.2--C--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup-
.9--X.sup.10--X.sup.11--X.sup.12--X.sup.13--C--X.sup.15--X.sup.16--
(18c)
wherein, X.sup.1 is selected from an amino acid; X.sup.2 is
selected from an amino acid; X.sup.3 is C; X.sup.4 is selected from
an amino acid comprising an aromatic side chain or a large
hydrophobic side chain; X.sup.5 is selected from an amino acid
comprising a large hydrophobic side chain; X.sup.6 is selected from
an amino acid; X.sup.7 is selected from an amino acid; X.sup.8 is
P; X.sup.9 is G; X.sup.10 is selected from an amino acid; X.sup.11
is selected from an amino acid; X.sup.12 is selected from an amino
acid; X.sup.13 is selected from an amino acid comprising an
aromatic side chain or a large hydrophobic side chain; X.sup.14 is
C; X.sup.15 is selected from an amino acid; and X.sup.16 is
selected from an amino acid comprising a large hydrophobic side
chain.
Aspect 725. The IL-2R.alpha. ligand of aspect 724, wherein,
X.sup.1 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.2 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.3 is C;
X.sup.4 is selected from F, H, I, L, M, V, W, and Y;
X.sup.5 is selected from F, I, L, M, V, W, and Y;
X.sup.6 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.8 is P;
X.sup.9 is G;
X.sup.10 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.11 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.12 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.13 is selected from F, H, I, L, M, V, W, and Y;
X.sup.14 is C;
X.sup.15 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y; and
X.sup.16 is selected from F, I, L, M, V, W, and Y.
Aspect 726. The IL-2R.alpha. ligand of any one of aspects 724 to
725, wherein X.sup.1 is selected from A, H, Q, R, T, and V.
Aspect 727. The IL-2R.alpha. ligand of any one of aspects 724 to
726, wherein X.sup.2 is selected from T, G, L, D, and K.
Aspect 728. The IL-2R.alpha. ligand of any one of aspects 724 to
727, wherein X.sup.3 is C.
Aspect 729. The IL-2R.alpha. ligand of any one of aspects 724 to
728, wherein X.sup.4 is selected from H, T, P, A, F, Q, and Y.
Aspect 730. The IL-2R.alpha. ligand of any one of aspects 724 to
729, wherein X.sup.5 is selected from L, W, G, I, E, M, and R.
Aspect 731. The IL-2R.alpha. ligand of any one of aspects 724 to
730, wherein X.sup.6 is selected from L, T, S, M, and N.
Aspect 732. The IL-2R.alpha. ligand of any one of aspects 724 to
731, wherein X.sup.7 is selected from A, K, D, E, W, T, and S.
Aspect 733. The IL-2R.alpha. ligand of any one of aspects 724 to
732, wherein X.sup.8 is P.
Aspect 734. The IL-2R.alpha. ligand of any one of aspects 724 to
733, wherein X.sup.9 is G.
Aspect 735. The IL-2R.alpha. ligand of any one of aspects 724 to
734, wherein X.sup.10 is selected from V, A, S, T, D, Q, and V.
Aspect 736. The IL-2R.alpha. ligand of any one of aspects 724 to
735, wherein X.sup.11 is selected from D, E, W, S, R, and I.
Aspect 737. The IL-2R.alpha. ligand of any one of aspects 724 to
736, wherein X.sup.12 is selected from N, W, G, V, P, and A.
Aspect 738. The IL-2R.alpha. ligand of any one of aspects 724 to
737, wherein X.sup.13 is selected from T, V, P, F, Y, and W.
Aspect 739. The IL-2R.alpha. ligand of any one of aspects 724 to
738, wherein X.sup.14 is C.
Aspect 740. The IL-2R.alpha. ligand of any one of aspects 724 to
738, wherein X.sup.14 is selected from I, S, P, D, H, T, and V.
Aspect 741. The IL-2R.alpha. ligand of any one of aspects 724 to
738, wherein X.sup.14 is selected from F, L, N, I, T, and G.
Aspect 742. The IL-2R.alpha. ligand of any one of aspects 724 to
741, wherein X.sup.1 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 743. The IL-2R.alpha. ligand of any one of aspects 724 to
742, wherein X.sup.2 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 744. The IL-2R.alpha. ligand of any one of aspects 724 to
743, wherein X.sup.3 is C.
Aspect 745. The IL-2R.alpha. ligand of any one of aspects 724 to
744, wherein X.sup.4 is selected from F, H, I, L, M, V, W, and
Y.
Aspect 746. The IL-2R.alpha. ligand of any one of aspects 724 to
744, wherein X.sup.4 is selected from F, W, and Y.
Aspect 747. The IL-2R.alpha. ligand of any one of aspects 724 to
746, wherein X.sup.5 is selected from F, I, L, M, V, W, and Y.
Aspect 748. The IL-2R.alpha. ligand of any one of aspects 724 to
747, wherein X.sup.6 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 749. The IL-2R.alpha. ligand of any one of aspects 724 to
748, wherein X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 750. The IL-2R.alpha. ligand of any one of aspects 724 to
749, wherein X.sup.8 is P.
Aspect 751. The IL-2R.alpha. ligand of any one of aspects 724 to
750, wherein X.sup.9 is G.
Aspect 752. The IL-2R.alpha. ligand of any one of aspects 724 to
751, wherein X.sup.10 is selected from A, D, E, F, G, H, I, K, L,
M, N, P, Q, R, S, T, V, W, and Y.
Aspect 753. The IL-2R.alpha. ligand of any one of aspects 724 to
752, wherein X.sup.11 is selected from A, D, E, F, G, H, I, K, L,
M, N, P, Q, R, S, T, V, W, and Y.
Aspect 754. The IL-2R.alpha. ligand of any one of aspects 724 to
753, wherein X.sup.12 is selected from A, D, E, F, G, H, I, K, L,
M, N, P, Q, R, S, T, V, W, and Y.
Aspect 755. The IL-2R.alpha. ligand of any one of aspects 724 to
754, wherein X.sup.13 is selected from F, H, I, L, M, V, W, and
Y.
Aspect 756. The IL-2R.alpha. ligand of any one of aspects 724 to
754, wherein X.sup.13 is selected from F, W, and Y.
Aspect 757. The IL-2R.alpha. ligand of any one of aspects 724 to
756, wherein X.sup.14 is C.
Aspect 758. The IL-2R.alpha. ligand of any one of aspects 724 to
757, wherein X.sup.15 is selected from A, D, E, F, G, H, I, K, L,
M, N, P, Q, R, S, T, V, W, and Y.
Aspect 759. The IL-2R.alpha. ligand of any one of aspects 724 to
758, wherein X.sup.16 is selected from F, I, L, M, V, W, and Y.
Aspect 760. The IL-2R.alpha. ligand of aspect 724, wherein X.sup.3
is C, X.sup.8 is P, X.sup.9 is G, and X.sup.14 is C.
Aspect 761. The IL-2R.alpha. ligand of aspect 724, wherein,
X.sup.1 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.2 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.3 is C;
X.sup.4 is selected from F, H, W, and Y;
X.sup.5 is selected from F, I, L, M, V, W, and Y;
X.sup.6 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.8 is P;
X.sup.9 is G;
X.sup.10 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.11 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.12 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.13 is selected from F, H, W, and Y;
X.sup.14 is C;
X.sup.15 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y; and
X.sup.16 is selected from F, I, L, M, V, W, and Y.
Aspect 762. The IL-2R.alpha. ligand of aspect 724, wherein the
IL-2R.alpha. ligand comprises an amino acid sequence selected from
any one of SEQ ID NO: 217 to SEQ ID NO: 224:
TABLE-US-00043 SEQ ID NO: 217 A T C H L L A P G V D N T C I F SEQ
ID NO: 218 H G C T L T K P G A E W V C S F SEQ ID NO: 219 Q L C P W
S D P G S W G P C P L SEQ ID NO: 220 R D C A G M E P G T S V F C D
N SEQ ID NO: 221 R D C F I L E P G T S V Y C D L SEQ ID NO: 222 T D
C Q E T W P G D R P W C H I SEQ ID NO: 223 V K C F M S T P G Q I A
Y C T T SEQ ID NO: 224 V K C Y R N S P G V E A Y C V G
Aspect 763. The IL-2R.alpha. ligand of any one of aspects 724 to
762, wherein,
the amino acid sequence independently comprises from 1 to 4
glycines (G) (SEQ ID NO: 1041) on the N-terminus, on the
C-terminus, or on both the N- and C-termini;
the amino acid sequence comprises a truncated amino acid sequence;
or
the amino acid sequence comprises a truncated amino acid sequence,
wherein the truncated amino acid sequence independently comprises
from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on
the C-terminus, or on both the N- and C-termini.
Aspect 764. The IL-2R.alpha. ligand of any one of aspects 762 to
763, wherein from 1 to 5 of the amino acids is independently
substituted with another amino acid.
Aspect 765. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises the amino acid sequence
of Formula (19a) (SEQ ID NO: 225), or the amino acid sequence of
Formula (19b) (SEQ ID NO: 226):
--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10-
--X.sup.11--X.sup.12-- (19a)
--X.sup.1--C--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup-
.9--X.sup.10--X.sup.11--X.sup.12--C--X.sup.14-- (19b)
wherein, X.sup.1 is selected from an amino acid; X.sup.2 is C;
X.sup.3 is selected from an amino acid comprising an acidic side
chain or a polar/neutral side chain; X.sup.4 is selected from an
amino acid comprising an acidic side chain or a polar/neutral side
chain; X.sup.5 is selected from an amino acid comprising a large
hydrophobic side chain; X.sup.6 is selected from an amino acid
comprising a polar/neutral side chain; X.sup.7 is selected from an
amino acid; X.sup.8 is selected from an amino acid; X.sup.9 is
selected from an amino acid comprising a large hydrophobic side
chain; X.sup.10 is selected from an amino acid; X.sup.11 is
selected from an amino acid; X.sup.12 is selected from an amino
acid; X.sup.13 is C; and X.sup.14 is selected from an amino
acid.
Aspect 766. The IL-2R.alpha. ligand of aspect 765, wherein,
X.sup.1 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.2 is C;
X.sup.3 is selected from D, E, N, Q, S, T, and Y;
X.sup.4 is selected from D, E, N, Q, S, T, and Y;
X.sup.5 is selected from F, I, L, M, V, W, and Y;
X.sup.6 is selected from N, Q, S, T, and Y;
X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.8 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.9 is selected from F, I, L, M, V, W, and Y;
X.sup.10 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.11 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.12 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.13 is C; and
X.sup.14 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y.
Aspect 767. The IL-2R.alpha. ligand of any one of aspects 765 to
766, wherein X.sup.1 is selected from D, P, S, T, W, and Y.
Aspect 768. The IL-2R.alpha. ligand of any one of aspects 765 to
767, wherein X.sup.2 is C.
Aspect 769. The IL-2R.alpha. ligand of any one of aspects 765 to
768, wherein X.sup.3 is selected from L, Q, M, E, W, and H.
Aspect 770. The IL-2R.alpha. ligand of any one of aspects 765 to
769, wherein X.sup.4 is selected from D, R, S, E, and L.
Aspect 771. The IL-2R.alpha. ligand of any one of aspects 765 to
770, wherein X.sup.5 is selected from L, P, F, and V.
Aspect 772. The IL-2R.alpha. ligand of any one of aspects 765 to
771, wherein X.sup.6 is selected from R, A, K, H, and W.
Aspect 773. The IL-2R.alpha. ligand of any one of aspects 765 to
772, wherein X.sup.7 is selected from G, E, K, R, D, G, and Q.
Aspect 774. The IL-2R.alpha. ligand of any one of aspects 765 to
773, wherein X.sup.8 is selected from T, Y, S, M, Q, and D.
Aspect 775. The IL-2R.alpha. ligand of any one of aspects 765 to
774, wherein X.sup.9 is selected from V, Y, and D.
Aspect 776. The IL-2R.alpha. ligand of any one of aspects 765 to
775, wherein X.sup.10 is selected from G, S, E, N, and Y.
Aspect 777. The IL-2R.alpha. ligand of any one of aspects 765 to
776, wherein X.sup.11 is selected from M, Q, W, V, E, N, R, L, and
M.
Aspect 778. The IL-2R.alpha. ligand of any one of aspects 765 to
777, wherein X.sup.12 is selected from V, Q, W, V, E, N, R, L, and
M.
Aspect 779. The IL-2R.alpha. ligand of any one of aspects 765 to
778, wherein X.sup.13 is C.
Aspect 780. The IL-2R.alpha. ligand of any one of aspects 765 to
779, wherein X.sup.14 is selected from Q, L, D, N, I, P, and F.
Aspect 781. The IL-2R.alpha. ligand of any one of aspects 765 to
780, wherein X.sup.1 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 782. The IL-2R.alpha. ligand of any one of aspects 765 to
781, wherein X.sup.2 is C.
Aspect 783. The IL-2R.alpha. ligand of any one of aspects 765 to
782, wherein X.sup.3 is selected from H, N, Q, S, T, and Y.
Aspect 784. The IL-2R.alpha. ligand of any one of aspects 765 to
783, wherein X.sup.3 is selected from D and E.
Aspect 785. The IL-2R.alpha. ligand of any one of aspects 765 to
783, wherein X.sup.3 is selected from Q and E.
Aspect 786. The IL-2R.alpha. ligand of any one of aspects 765 to
785, wherein X.sup.4 is selected from D and E.
Aspect 787. The IL-2R.alpha. ligand of any one of aspects 765 to
786, wherein X.sup.5 is L.
Aspect 788. The IL-2R.alpha. ligand of any one of aspects 765 to
787, wherein X.sup.6 is selected from R, H, and K.
Aspect 789. The IL-2R.alpha. ligand of any one of aspects 765 to
788, wherein X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 790. The IL-2R.alpha. ligand of any one of aspects 765 to
789, wherein X.sup.8 is selected from A, D, E, F, G, H, I, K, L, M,
N, P, Q, R, S, T, V, W, and Y.
Aspect 791. The IL-2R.alpha. ligand of any one of aspects 765 to
790, wherein X.sup.9 is Y.
Aspect 792. The IL-2R.alpha. ligand of any one of aspects 765 to
791, wherein X.sup.10 is selected from A, G, P, S, and T.
Aspect 793. The IL-2R.alpha. ligand of any one of aspects 765 to
792, wherein X.sup.11 is selected from A, D, E, F, G, H, I, K, L,
M, N, P, Q, R, S, T, V, W, and Y.
Aspect 794. The IL-2R.alpha. ligand of any one of aspects 765 to
793, wherein X.sup.12 is selected from F, I, L, M, V, W, and Y.
Aspect 795. The IL-2R.alpha. ligand of any one of aspects 765 to
793, wherein X.sup.12 is selected from V, L, and M.
Aspect 796. The IL-2R.alpha. ligand of any one of aspects 765 to
795, wherein X.sup.13 is C.
Aspect 797. The IL-2R.alpha. ligand of any one of aspects 765 to
796, wherein X.sup.14 is selected from F, I, L, M, V, W, and Y.
Aspect 798. The IL-2R.alpha. ligand of any one of aspects 765 to
796, wherein X.sup.14 is selected from F, I, and L.
Aspect 799. The IL-2R.alpha. ligand of any one of aspects 765 to
766, wherein X.sup.2 is C, X.sup.5 is L, and X.sup.1 is C.
Aspect 800. The IL-2R.alpha. ligand of aspect 765, wherein,
X.sup.1 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.2 is C;
X.sup.3 is selected from D, E, N, Q, S, T, and Y;
X.sup.4 is selected from D, E, N, Q, S, T, and Y;
X.sup.5 is L;
X.sup.6 is selected from A, G, H, K, P, S, and T;
X.sup.7 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.8 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y;
X.sup.9 is selected from F, I, L, M, V, W, and Y;
X.sup.10 is selected from A, G, P, S, and T;
X.sup.11 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,
S, T, V, W, and Y; and
X.sup.12 is selected from F, I, L, M, V, W, and Y;
X.sup.13 is C; and
X.sup.14 is selected from F, I, L, M, V, W, and Y.
Aspect 801. The IL-2R.alpha. ligand of aspect 765, wherein the
IL-2R.alpha. ligand comprises an amino acid sequence selected from
any one of SEQ ID NO: 227 to SEQ ID NO: 234:
SEQ ID NO: 227 D C L D L R G T V G M V C Q
SEQ ID NO: 228 P C Q R L A E Y Y S Q Q C L
SEQ ID NO: 229 S C M D L K G S V G W V C D
SEQ ID NO: 230 T C E S L A K M Y E V E C N
SEQ ID NO: 231 T C E S L A R M Y N E N C I
SEQ ID NO: 232 W C W E P H D Q Y Y V R C P
SEQ ID NO: 233 Y C H D F K G T V G T L C I
SEQ ID NO: 234 G C Q L V W Q D D S Y M C F Y
Aspect 802. The IL-2R.alpha. ligand of any one of aspects 765 to
801, wherein,
the amino acid sequence independently comprises from 1 to 4
glycines (G) (SEQ ID NO: 1041) on the N-terminus, on the
C-terminus, or on both the N- and C-termini;
the amino acid sequence comprises a truncated amino acid sequence;
or
the amino acid sequence comprises a truncated amino acid sequence,
wherein the truncated amino acid sequence independently comprises
from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on
the C-terminus, or on both the N- and C-termini.
Aspect 803. The IL-2R.alpha. ligand of any one of aspects 801 to
802, wherein from 1 to 5 of the amino acids is independently
substituted with another amino acid.
Aspect 804. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises the amino acid sequence
of Formula (20a) (SEQ ID NO: 235), or the amino acid sequence of
Formula (20b) (SEQ ID NO: 236):
--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup.9--X.sup.10-
--X.sup.11--X.sup.12-- (20a)
--X.sup.1--C--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X.sup.8--X.sup-
.9--X.sup.10--X.sup.11--X.sup.12--C--X.sup.14-- (20b)
wherein, X.sup.1 is W; X.sup.2 is C; X.sup.3 is selected from F, I,
L, M, V, W, and Y; X.sup.4 is G; X.sup.5 is Q; X.sup.6 is P;
X.sup.7 is L; X.sup.8 is selected from F, I, L, M, V, W, and Y;
X.sup.9 is R; X.sup.10 is selected from H, N, Q, F, I, L, M, V, W,
and Y; X.sup.11 is G; X.sup.12 is S; X.sup.13 is C; and X.sup.14 is
K.
Aspect 805. The IL-2R.alpha. ligand of aspect 804, wherein X.sup.3
is selected from I and V.
Aspect 806. The IL-2R.alpha. ligand of any one of aspects 804 to
805, wherein X.sup.8 is selected from F and Y.
Aspect 807. The IL-2R.alpha. ligand of any one of aspects 804 to
806, wherein X.sup.10 is selected from F, I, L, M, N, Q, S, T, V,
W, and Y.
Aspect 808. The IL-2R.alpha. ligand of any one of aspects 804 to
807, wherein X.sup.10 is selected from L and Q.
Aspect 809. The IL-2R.alpha. ligand of aspect 804, wherein X.sup.1
is W, X.sup.2 is C, X.sup.4 is G, X.sup.5 is Q, X.sup.6 is P,
X.sup.7 is L, X.sup.9 is R, X.sup.11 is G, X.sup.12 is 5S, X.sup.11
is C, and X.sup.14 is K.
Aspect 810. The IL-2R.alpha. ligand of aspect 804, wherein,
X.sup.1 is W;
X.sup.2 is C;
X.sup.3 is selected from I and V;
X.sup.4 is G;
X.sup.5 is Q;
X.sup.6 is P;
X.sup.7 is L;
X.sup.8 can be selected from F and Y;
X.sup.9 is R;
X.sup.10 is selected from F, H, I, L, M, N, Q, S, T, V, W, and
Y;
X.sup.11 is G;
X.sup.12 is S;
X.sup.13 is C; and
X.sup.14 is K.
Aspect 811. The IL-2R.alpha. ligand of aspect 804, wherein the
IL-2R.alpha. ligand comprises an amino acid sequence selected from
any one of SEQ ID NO: 237 to SEQ ID NO: 307:
TABLE-US-00044 SEQ ID NO: 237 W C I G Q P L F R Q G S C K SEQ ID
NO: 238 W C V G Q P L Y R L G S C K SEQ ID NO: 239 W D Q F Q L G W
E A G V A A SEQ ID NO: 240 F L P W P V Y F S Q V L G G G SEQ ID NO:
241 Y V M C S A F G C K S I SEQ ID NO: 242 H V I C S V N G G C R G
SEQ ID NO: 243 I R F C L R S E P T A C W I V SEQ ID NO: 244 I R C R
Y E K Q S G I C L F SEQ ID NO: 245 G G C S L V W A D S W V C I F
SEQ ID NO: 246 G C S L M W Q D G W W V C I SEQ ID NO: 247 E W E C R
F L P G R R G C S L F SEQ ID NO: 248 K G C T L Q N P G S G W V C L
F SEQ ID NO: 249 T C R L K R S G P N S W E C I SEQ ID NO: 250 W C I
G Q P L F R Q G S C K SEQ ID NO: 251 A V S C N S W R C I P W SEQ ID
NO: 252 A V C C D G N S C R R C SEQ ID NO: 253 F V H C S L M G C W
C G SEQ ID NO: 254 R C L D L G G S V G L V C F SEQ ID NO: 255 V C F
N F R G T V G R H C W SEQ ID NO: 256 V R C R Q N E P G G A Y W C S
S SEQ ID NO: 257 C V L R E G A E G W E C V W R SEQ ID NO: 258 C R M
M Q G T Y G W T C L F SEQ ID NO: 259 C I L N D T I Q G W V C I Y
SEQ ID NO: 260 C T L Y R S A P G V W L C I F SEQ ID NO: 261 C L V F
D Q Y G N Y K R R C SEQ ID NO: 262 I V C C N M F G C H T C R N SEQ
ID NO: 263 Q V C C T S R G C R V C A P V SEQ ID NO: 264 R V C C S M
V G C R S C N L SEQ ID NO: 265 R V C C T F A G C R V C H K SEQ ID
NO: 266 R V C C T S D G C R G C R Q SEQ ID NO: 267 T V C C T V Q G
C W P C S R SEQ ID NO: 268 V C C H Q T F G C Y R C K Q SEQ ID NO:
269 C V V C S A L G C R A C V P R SEQ ID NO: 270 V W D C F V R G W
E V A A V A V G E SEQ ID NO: 271 L T C L I F K P G T H R H C P V
SEQ ID NO: 272 R Y C S P L I P G S A L G C P R SEQ ID NO: 273 I R C
R L D P P G S Y K T C V F SEQ ID NO: 274 R G V I C N H A G C R I W
Y G SEQ ID NO: 275 T T Q S C T L R Y C W L L Q SEQ ID NO: 276 W W I
S C L R D L R C L E Y F SEQ ID NO: 277 R H A C K T W Y R M C I V S
SEQ ID NO: 278 A V S C S R L T G R C H S L SEQ ID NO: 279 W V A C N
R V T G S C R P I SEQ ID NO: 280 S H G V C C T Q S S C R S C R SEQ
ID NO: 281 W V A C N R L S G C C R P I SEQ ID NO: 282 H T V C C Q D
W G C R S C S G SEQ ID NO: 283 M A C C T P R G C R P C SEQ ID NO:
284 R S V C C S S Y G C R A C F G SEQ ID NO: 285 C K L T C T S S T
C S C V F SEQ ID NO: 286 C M L K C T N A I C E C I F SEQ ID NO: 287
C R V W C N Q A E C M C I F SEQ ID NO: 288 S R C S F D V T K Q E C
V F SEQ ID NO: 289 L E C Q P Y R G P L Y Y C Q D SEQ ID NO: 290 S I
C C T P Q L C H S C D G SEQ ID NO: 291 T T C C T S E G C H K C I T
L SEQ ID NO: 292 C V A C S S D G C S P I I C SEQ ID NO: 293 A I C S
E D E G G E L C C W H SEQ ID NO: 294 H E I C C G P P G C H S C S V
T SEQ ID NO: 295 L S V C S C P P G Q L Y C M V E SEQ ID NO: 296 S T
W C C L H P G V G E C Q A V SEQ ID NO: 297 V T Q C F D G P G S F R
C C Y Q SEQ ID NO: 298 R Q C N C L S P G E L V N C Q Q SEQ ID NO:
299 M V S C T D L G C V V V G G G SEQ ID NO: 300 V V H C L Q S G C
Y S V G S G SEQ ID NO: 301 T I K C G S S G W C W V E A G SEQ ID NO:
302 M V S C T D L G C V V V G G G SEQ ID NO: 303 H E I C C G P P G
C H S C S V T SEQ ID NO: 304 L S V C S C P P G Q L Y C M V E SEQ ID
NO: 305 S T W C C L H P G V G E C Q A V SEQ ID NO: 306 V T Q C F D
G P G S F R C C Y Q SEQ ID NO: 307 R Q C N C L S P G E L V N C Q
Q
Aspect 812. The IL-2R.alpha. ligand of any one of aspects 804 to
811, wherein,
the amino acid sequence independently comprises from 1 to 4
glycines (G) (SEQ ID NO: 1041) on the N-terminus, on the
C-terminus, or on both the N- and C-termini;
the amino acid sequence comprises a truncated amino acid sequence;
or
the amino acid sequence comprises a truncated amino acid sequence,
wherein the truncated amino acid sequence independently comprises
from 1 to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on
the C-terminus, or on both the N- and C-termini.
Aspect 813. The IL-2R.alpha. ligand of any one of aspects 811 to
812, wherein from 1 to 5 of the amino acids is independently
substituted with another amino acid.
Aspect 814. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises an amino acid sequence
selected from any one of SEQ ID NO: 400 to SEQ ID NO: 423:
TABLE-US-00045 SEQ ID NO: 400 W D D F I L G W E A G V A A V G E V
SEQ ID NO: 401 F L P W P V Y F S Q V L G G R R SEQ ID NO: 402 Y V M
C S A F G C K S I G G SEQ ID NO: 403 H V I C S V N G G C R G G G
SEQ ID NO: 404 G G I R F C L R S E P T A C W I V G G SEQ ID NO: 405
G G I R C R Y E K Q S G I C L F G G SEQ ID NO: 423 G G G G C S L V
W A D S W V C I F G G SEQ ID NO: 406 G G G C S L M W Q D G W W V C
I G G SEQ ID NO: 407 G G E W E C R F L P G R R G C S L F G G SEQ ID
NO: 408 G G K G C T L Q N P G S G W V C L F G G SEQ ID NO: 409 G G
T C R L K R S G P N S W E C I G G SEQ ID NO: 410 G G W C I G Q P L
F R Q G S C K G G SEQ ID NO: 411 F V L C G L Q G C R S G G SEQ ID
NO: 412 F V P W D E Y F L Q I L G G SEQ ID NO: 413 G G G W V I C S
A L G C P F G G SEQ ID NO: 414 G G G R R F C L R S E P T A C W T V
G G SEQ ID NO: 415 G G G S R C S L V W A D S W V C I F G G SEQ ID
NO: 416 G G D W E C L F L P G R R G C T L F G G SEQ ID NO: 417 F I
P W D E Y F A Q L L G G SEQ ID NO: 418 F V P W D V Y F S Q I L G G
SEQ ID NO: 419 F I P W D E Y F K Q V L G G SEQ ID NO: 420 F V P W P
E Y F L Q I M G G SEQ ID NO: 421 F I P W E E Y F S Q L L G G SEQ ID
NO: 422 F I P W P E Y F S Q L L G G
Aspect 815. The IL-2R.alpha. ligand of aspect 814, wherein the
amino acid sequence comprises a truncated amino acid sequence.
Aspect 816. The IL-2R.alpha. ligand of any one of aspects 814 to
815, wherein the amino acid sequence independently comprises from 1
to 4 glycines (G) (SEQ ID NO: 1041) on the N-terminus, on the
C-terminus, or on both the N- and C-termini.
Aspect 817. The IL-2R.alpha. ligand of any one of aspects 814 to
816, wherein from 1 to 5 of the amino acids is independently
substituted with another amino acid.
Aspect 818. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises an amino acid sequence
selected from any one of SEQ ID NO: 1 to SEQ ID NO: 307 and SEQ ID
NO. 400 to SEQ ID NO: 423.
Aspect 819. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises an amino acid sequence
having greater than 70%, greater than 75%, greater than 80%,
greater than 85%, greater than 90%, or greater than 95% sequence
similarity to any one of SEQ ID NO: 1 to SEQ ID NO: 307 and SEQ ID
NO. 400 to SEQ ID NO: 423.
Aspect 820. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises a truncated amino acid
sequence of any one of SEQ ID NO: 1 to SEQ ID NO: 307 and SEQ ID
NO. 400 to SEQ ID NO: 423.
Aspect 821. The IL-2R.alpha. ligand of any one of aspects 1 to 6,
wherein the IL-2R.alpha. ligand comprises an amino acid sequence
having greater than 70%, greater than 75%, greater than 80%,
greater than 85%, greater than 90%, or greater than 95% sequence
similarity to a truncated amino acid sequence of any one of SEQ ID
NO: 1 to SEQ ID NO: 307 and SEQ ID NO. 400 to SEQ ID NO: 423.
Aspect 822. A compound comprising an IL-2R.alpha. ligand of any one
of aspects 1 to 821.
Aspect 823. The compound of aspect 822, wherein the compound is
selected from a peptide, a conjugate, a fusion protein, and a
single chain tandem peptide.
Aspect 825. The compound of aspect 823, wherein the compound is a
peptide.
Aspect 825. The compound of aspect 824, wherein the peptide has a
molecular weight within a range from 500 Daltons to 15,000
Daltons.
Aspect 826. The compound of any one of aspects 825 to 826, wherein
the peptide comprises from 5 amino acids to 4,000 amino acids.
Aspect 827. The compound of aspect 823, wherein the compound
comprises a conjugate.
Aspect 828. The compound of aspect 827, wherein the conjugate
comprises at least one IL-2R.alpha. ligand.
Aspect 829. The compound of aspect 827, wherein the conjugate
comprises: at least two IL-2R.alpha. ligands; and at least one
linker attached to each of the at least two IL-2R.alpha.
ligands.
Aspect 830. The compound of any one of aspects 823 to 829, wherein
the conjugate comprises at least one IL-2R.beta. ligand and/or at
least one IL-2R.gamma.c ligand.
Aspect 831. The compound of any one of aspects 823 to 829, wherein
the conjugate comprises: at least two IL-2R.beta. ligands; and at
least one linker attached to each of the at least two IL-2R.beta.
ligands.
Aspect 832. The compound of aspect 823, wherein the conjugate
comprises: at least two IL-2R.gamma.c ligands; and at least one
linker attached to each of the at least two IL-2R.gamma.c
ligands.
Aspect 833. The compound of aspect 823, wherein the conjugate
comprises: at least one IL-2R.beta. ligand; at least one
IL-2R.gamma.c ligand; and at least one linker attached to the at
least one IL-2R.beta. ligand and to the at least one IL-2R.gamma.c
ligand.
Aspect 834. The compound of any one of aspects 823 to 833, wherein
the conjugate comprises at least one moiety, amino acid, or
polypeptide configured to modify a property of the conjugate.
Aspect 835. The compound of aspect 834, wherein the property is
selected from aqueous solubility, polarity, lipophilicity,
pharmacokinetic profile, targeting, bioavailability, pH-dependent
binding, bioactivity, pharmacodynamics, cellular activity,
metabolism, therapeutic efficacy, and caging (reversible
incapacitation).
Aspect 836. The compound of any one of aspects 834 to 835, wherein
the at least one moiety is cleavable in vivo.
Aspect 837. The compound of any one of aspects 834 to 836, wherein
the at least one moiety comprises an irreversibly cleavable
promoiety.
Aspect 838. The compound of aspect 837, wherein the promoiety is
configured to be releasable in a target-specific environment.
Aspect 839. The compound of aspect 838, wherein the target-specific
environment comprises an enzyme, pH, or a combination thereof.
Aspect 840. The compound of any one of aspects 834 to 839, wherein
the moiety comprises a small molecule, polymer, a peptide, or an
antibody.
Aspect 841. The compound of any one of aspects 834 to 840, wherein
the moiety comprises a pharmacokinetic moiety.
Aspect 842. The compound of aspect 841, wherein the pharmacokinetic
moiety comprises a polyethylene glycol.
Aspect 843. The compound of any one of aspects 834 to 842, wherein
the moiety comprises a tumor-targeting moiety.
Aspect 844. The compound of aspect 843, wherein the tumor-targeting
moiety comprises a tumor-specific antibody, a tumor-specific
antibody fragment, a tumor-specific protein, or a tumor-specific
peptide.
Aspect 845. The compound of any one of aspects 834 to 844, wherein
the moiety comprises an immune cell-targeting moiety.
Aspect 846. The compound of any one of aspects 822 to 845, wherein
the compound comprises a linker covalently bound to the
IL-2R.alpha. ligand.
Aspect 847. The compound of aspect 846, wherein the linker is
selected from a peptide having from 2 amino acids to 200 amino
acids.
Aspect 848. The compound of any one of aspects 846 to 847, wherein
the linker comprises a polyethylene glycol.
Aspect 849. The compound of any one of aspects 822 to 848, wherein
the compound comprises a heteromer, wherein the heteromer
comprises:
an IL-2R.alpha. ligand;
an IL-2R.beta. ligand;
an IL-2R.gamma.c ligand; and
a linker;
wherein each of the IL-2R.alpha. ligand, the IL-2R.beta. ligand and
the IL-2R.gamma.c ligand comprise an amino-terminus (N-terminus), a
carboxy terminus (C-terminus), and an amino acid side chain;
wherein the IL-2R.alpha. ligand is bonded to the linker through the
amino-terminus (N-terminus), the carboxy terminus (C-terminus), an
amino acid side chain, or a combination of any of the foregoing;
and
wherein the IL-2R.beta. ligand is bonded to the linker through the
amino-terminus (N-terminus), the carboxy terminus (C-terminus), an
amino acid side chain, or a combination of any of the foregoing;
and
wherein the IL-2R.gamma.c ligand is bonded to the linker through
the amino-terminus (N-terminus), the carboxy terminus (C-terminus),
an amino acid side chain, or a combination of any of the
foregoing.
Aspect 850. The compound of any one of aspects 822 to 848, wherein
the compound comprises a heteromer, wherein the heteromer
comprises:
an IL-2R.alpha. ligand;
an IL-2R.beta. ligand;
an IL-2R.gamma.c ligand; and
a linker;
wherein each of the IL-2R.alpha. ligand, the IL-2R.beta. ligand,
and the IL-2R.gamma.c ligand comprises an amino-terminus
(N-terminus) and a carboxy terminus (C-terminus); and
wherein each of the IL-2R.alpha. ligand, the IL-2R.beta. ligand,
and the IL-2R.gamma.c ligand is covalently bound to the linker.
Aspect 851. The compound of aspect 850, wherein each of the
IL-2R.alpha. ligand, the IL-2R.beta. ligand, and the IL-2R.gamma.c
ligand is covalently bound to the linker through the respective
C-terminus and/or through the respective N-terminus.
Aspect 852. The compound of aspect 850, wherein,
the IL-2R.alpha. ligand is covalently bound to the linker through
an amino acid side chain;
the IL-2R.beta. ligand is covalently bound to the linker through an
amino acid side chain; and/or
the IL-2R.gamma.c ligand is covalently bound to the linker through
an amino acid side chain.
Aspect 853. The compound of aspect 850, wherein,
the IL-2R.alpha. ligand is covalently bound to the linker through
an amino acid side chain, through the C-terminus, or through the
N-terminus;
the IL-2R.beta. ligand is covalently bound to the linker through an
amino acid side chain, through the C-terminus, or through the
N-terminus; and
the IL-2R.gamma.c ligand is covalently bound to the linker through
an amino acid side chain, through the C-terminus, or through the
N-terminus.
Aspect 854. The compound of any one of aspects 850 to 853, wherein
the heteromer is configured to activate the IL-2 receptor.
Aspect 855. The compound of any one of aspects 850 to 853, wherein
the linker is configured such that the heteromer activates the IL-2
receptor.
Aspect 856. The compound of any one of aspects 822 to 855, wherein
the compound is an IL-2R agonist.
Aspect 857. The compound of any one of aspects 822 to 855, wherein
the compound is an IL-2R antagonist.
Aspect 858. The compound of any one of aspects 822 to 855, wherein
the compound comprises a conformation configured to activate human
IL-2R.beta..gamma.c signaling pathways.
Aspect 859. The compound of any one of aspects 822 to 858, wherein
the compound comprises a single chain peptide.
Aspect 860. The compound of aspect 859, wherein the single chain
peptide comprises at least one IL-2R.beta. ligand.
Aspect 861. The compound of any one of aspects 859 to 860, wherein
the single chain peptide comprises: at least two IL-2R.beta.
ligands; and at least one linker attached to the at least two
IL-2R.beta. ligands.
Aspect 862. The compound of any one of aspects 859 to 861, wherein
the single chain peptide comprises a least one IL-2R.gamma.c
ligand.
Aspect 863. The compound of any one of aspects 859 to 862, wherein
the single chain peptide comprises: at least two IL-2R.gamma.c
ligands; and at least one linker attached to the at least two
IL-2R.gamma.c ligands.
Aspect 864. The compound of any one of aspects 859 to 863, wherein
the single chain tandem peptide comprises:
at least one IL-2R.alpha. ligand;
at least one IL-2R.beta. ligand;
at least one IL-2R.gamma.c ligand; and
at least one linker attached to the at least one IL-2R.alpha.
ligand, to the at least one IL-2R.beta. ligand, and to the at least
one IL-2R.gamma.c ligand.
Aspect 865. The compound of any one of aspects 822 to 864, wherein
the compound is a fusion protein.
Aspect 866. The compound of aspect 865, wherein the fusion protein
comprises:
at least one IL-2R.alpha. ligand;
at least one IL-2R.beta. ligand;
at least one IL-2R.gamma.c ligand; and
a peptide linker domain, wherein the peptide linker domain is bound
to the at least one IL-2R.alpha. ligand, to the at least one
IL-2R.beta. ligand, and to the at least one IL-2R.gamma.c
ligand.
Aspect 867. The compound of aspect 865, wherein,
each peptide linker domain has an amino-terminus (N-terminus) and a
carboxy terminus (C-terminus); and
the C-terminus of the IL-2R.alpha. ligand is fused through a
peptide bond to the N-terminus of the peptide linker domain, and
the C-terminus of the peptide linker domain is fused to a protein
fusion partner.
Aspect 868. The compound of aspect 867, wherein the protein fusion
partner comprises an IgG molecule, an IgG Fab fragment, or an Fc
fragment,
Aspect 868. The compound of any one of aspects 867 to 868, wherein
the protein fusion partner comprises IL-2, a variant of IL-2, a
mutant of IL-2, or an IL-2R agonist.
Aspect 870. The compound of aspect 865, wherein,
each peptide linker domain has an amino-terminus (N-terminus) and a
carboxy terminus (C-terminus); and
the N-terminus of the IL-2R.alpha. ligand is fused through a
peptide bond to the C-terminus of the peptide linker domain, and
the N-terminus of the peptide linker domain is fused to a protein
fusion partner.
Aspect 871. The compound of aspect 870 wherein the protein fusion
partner comprises an IgG molecule, an IgG Fab fragment, or an Fc
fragment,
Aspect 872. The compound of any one of aspects 870 to 871, wherein
the protein fusion partner comprises IL-2, a variant of IL-2, a
mutant of IL-2, or an IL-2R agonist.
Aspect 873. A nucleic acid encoding the fusion protein of aspect
865.
Aspect 874. The compound of any one of aspects 822 to 872, wherein
the compound comprises a label.
Aspect 875. The compound of aspect 874, wherein the label is
selected from a radioisotope, a fluorophore, or a combination
thereof.
Aspect 876. The compound of any one of aspects 822 to 875, wherein
the compound comprises a cage to protect peripheral tissues for the
toxicity of IL-2R activation.
Aspect 877. The compound of any one of aspects 822 to 876, wherein
the compound comprises a promoiety.
Aspect 878. The compound of aspect 877, wherein the promoiety
comprises a moiety configured to sustain a circulating reservoir of
the compound.
Aspect 879. The compound of any one of aspects 822 to 878, wherein
the compound comprises a moiety configured to target IL-2R-directed
immuno-stimulation of the effector immune cells in the tumor.
Aspect 880. The compound of any one of aspects 822 to 879, wherein
the compound comprises a cleavable moiety.
Aspect 881. The compound of aspect 880, wherein the cleavable
moiety is cleavable by electromagnetic radiation, thermal energy,
pH, or a combination of any of the foregoing.
Aspect 882. The compound of any one of aspects 822 to 881, wherein
the compound comprises a moiety that is toxic to cells having high
IL-2R.alpha. expression.
Aspect 883. The compound of aspect 882, wherein the cells having
high IL-2R.alpha. expression are Treg cells.
Aspect 884. The compound of aspect 882, wherein the toxic moiety is
a cleavable moiety.
Aspect 885. The compound of aspect 884, the cleavable moiety is
cleavable by electromagnetic radiation, thermal energy, pH, or a
combination of any of the foregoing.
Aspect 886. The compound of any one of aspects 882 to 885, wherein
the toxic moiety is activated by electromagnetic radiation, thermal
energy, pH, or a combination of any of the foregoing.
Aspect 887. The compound of any one of aspects 822 to 886, wherein
the compound comprises an imaging agent, a diagnostic agent, a
targeting agent, a therapeutic agent, or a combination of any of
the foregoing.
Aspect 888. A pharmaceutical composition comprising;
the IL-2R.alpha. ligand of any one of aspects 1 to 821;
a compound of any one of aspects 822 to 887; or
a combination of any of the foregoing.
Aspect 889. A method of treating cancer in a patient, comprising
administering to a patient in need of such treatment, a
therapeutically effective amount of the pharmaceutical composition
of aspect 880.
Aspect 890. A method of treating cancer in a patient, comprising
administering to a patient in need of such treatment, a
therapeutically effective amount of;
the IL-2R.alpha. ligand of any one of aspects 1 to 821;
the compound of any one of aspects 822 to 887; or
a combination of any of the foregoing.
Aspect 891. The method of any one of aspects 889 and 890, wherein
the cancer comprises a solid tumor.
Aspect 892. A method of treating an autoimmune disease in a
patient, comprising administering to a patient in need of such
treatment, a therapeutically effective amount of the pharmaceutical
composition of aspect 888.
Aspect 893. A method of treating an autoimmune disease in a
patient, comprising administering to a patient in need of such
treatment, a therapeutically effective amount of;
the IL-2R.alpha. ligand of any one of aspects 1 to 821;
the compound of any one of aspects 822 to 887; or
a combination of any of the foregoing.
Aspect 894. A method of treating an autoimmune disease in a
patient, comprising administering to a patient in need of such
treatment, a therapeutically effective amount of the pharmaceutical
composition of aspect 888.
Aspect 895. A method of treating an autoimmune disease in a
patient, comprising administering to a patient in need of such
treatment, a therapeutically effective amount of;
the IL-2R.alpha. ligand of any one of aspects 1 to 821;
the compound of any one of aspects 822 to 8887; or
a combination of any of the foregoing.
Aspect 896. A method of screening compounds for IL-2.alpha.
activity, comprising:
contacting a cell with, the IL-2R.alpha. ligand of any one of
aspects 1 to 821; the compound of any one of aspects 822 to 887; or
a combination of any of the foregoing. wherein the cell expresses
the IL-2.alpha. subunit; and
contacting the cell with a test compound; and
determining the activity of the test compound.
Aspect 897. A method of activating the human IL-2 receptor,
comprising contacting a cell expressing the human IL-2 receptor in
vivo with the IL-2R.alpha. ligand of any one of aspects 1 to 821 or
a compound comprising the IL-2R.alpha. ligand of any one of aspects
1 to 821.
Aspect 898. A method of activating the human IL-2 receptor in a
patient, comprising administering to a patient an effective amount
of the IL-2R.alpha. ligand of any one of aspects 1 to 821 or a
compound comprising the IL-2R.alpha. ligand of any one of aspects 1
to 821.
Aspect 899. A method of treating a disease in a patient, wherein
the IL-2 receptor signaling pathway is associated with the etiology
of the disease, comprising administering to a patient in need of
such treatment a therapeutically effective amount of the
IL-2R.alpha. ligand of any one of aspects 1 to 821 or a compound
comprising the IL-2R.alpha. ligand of any one of aspects 1 to
821.
Aspect 900. A method of treating a disease in a patient, wherein
activation of the IL-2 receptor is effective in treating the
disease, comprising administering to a patient in need of such
treatment a therapeutically effective amount of the IL-2R.alpha.
ligand of any one of aspects 1 to 821 or a compound comprising the
IL-2R.alpha. ligand of any one of aspects 1 to 821.
Aspect 901. A method of treating a disease in a patient, wherein
inhibition of the IL-2 receptor is effective in treating the
disease, comprising administering to a patient in need of such
treatment a therapeutically effective amount the IL-2R.alpha.
ligand of any one of aspects 1 to 821 or of a compound comprising
the IL-2R.alpha. ligand of any one of aspects 1 to 821.
Aspect 902. A method of treating a disease in a patient, wherein
cells expressing the IL-2R.alpha. subunit (CD25) are associated
with the etiology of the disease, comprising administering to a
patient in need of such treatment a therapeutically effective
amount of the IL-2R.alpha. ligand of any one of aspects 1 to 821 or
a compound comprising the IL-2R.alpha. ligand of any one of aspects
1 to 821.
Aspect 903. A method of treating a disease in a patient, wherein
binding to the IL-2R.alpha. subunit (CD25) is effective in treating
the disease, comprising administering to a patient in need of such
treatment a therapeutically effective amount the IL-2R.alpha.
ligand of any one of aspects 1 to 821 or of a compound comprising
the IL-2R.alpha. ligand of any one of aspects 1 to 821.
Aspect 904. A method of treating a disease in a patient, wherein
inhibiting binding of an IL-2R agonist to the IL-2R.alpha. subunit
(CD25) is effective in treating the disease, comprising
administering to a patient in need of such treatment a
therapeutically effective amount of the IL-2R.alpha. ligand of any
one of aspects 1 to 821 or a compound comprising the IL-2R.alpha.
ligand of any one of aspects 1 to 821.
Aspect 905. A method of treating a disease in a patient, wherein
reducing the sensitivity of Treg cells to IL-2 is effective in
treating the disease, comprising administering to a patient in need
of such treatment a therapeutically effective amount of the
IL-2R.alpha. ligand of any one of aspects 1 to 821 or a compound
comprising the IL-2R.alpha. ligand of any one of aspects 1 to
821.
Aspect 906. A method of treating a disease in a patient, wherein
inhibiting binding to the IL-2R.alpha. subunit (CD25) is effective
in treating the disease, comprising administering to a patient in
need of such treatment a therapeutically effective amount of the
IL-2R.alpha. ligand of any one of aspects 1 to 821 or a compound
comprising the IL-2R.alpha. ligand of any one of aspects 1 to
821.
Aspect 907. A method of treating a disease in a patient, wherein
the etiology of the disease is associated with activation of Treg
cells, comprising administering to a patient in need of such
treatment a therapeutically effective amount of the IL-2R.alpha.
ligand of any one of aspects 1 to 821 or a compound comprising the
IL-2R.alpha. ligand of any one of aspects 1 to 821.
Aspect 908. A method of treating a disease in a patient, wherein
the etiology of the disease is associated with cells exhibiting a
high IL-2R.alpha. expression, comprising administering to a patient
in need of such treatment a therapeutically effective amount of the
IL-2R.alpha. ligand of any one of aspects 1 to 821 or a compound
comprising the IL-2R.alpha. ligand of any one of aspects 1 to
821.
Aspect 909. A method of imaging cells expressing the IL-2R.alpha.
subunit comprising administering to a patient an effective amount
of the IL-2R.alpha. ligand of any one of aspects 1 to 821 or a
compound comprising the IL-2R.alpha. ligand of any one of aspects 1
to 821.
Aspect 910. A method of diagnosing a disease in a patient wherein
the disease is associated with cells expressing the IL-2R.alpha.
subunit comprising administering to a patient an effective amount
of the IL-2R.alpha. ligand of any one of aspects 1 to 821 or a
compound comprising the IL-2R.alpha. ligand of any one of aspects 1
to 821.
Aspect 911. A method of targeting a compound to cells expressing
the IL-2R.alpha. subunit comprising administering to a patient an
effective amount of the IL-2R.alpha. ligand of any one of aspects 1
to 821 or a compound comprising the IL-2R.alpha. ligand of any one
of aspects 1 to 821.
Aspect 912. A method of delivering a cytotoxic compound to cells
expressing the IL-2R.alpha. subunit comprising administering to a
patient an effective amount of the IL-2R.alpha. ligand of any one
of aspects 1 to 821 or a compound comprising a cytotoxic moiety and
the IL-2R.alpha. ligand of any one of aspects 1 to 821.
Aspect 913. The method of any one of aspects 897 to 912, wherein
the compound comprises the compound of any one of aspects 822 to
887.
Finally, it should be noted that there are alternative ways of
implementing the embodiments disclosed herein. Accordingly, the
present embodiments are to be considered as illustrative and not
restrictive, and the claims are not to be limited to the details
given herein but may be modified within the scope and equivalents
thereof.
SEQUENCE LISTINGS
1
SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 1041 <210>
SEQ ID NO 1 <211> LENGTH: 12 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (1)..(1) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain or an aromatic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (4)..(4) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(5)..(5) <223> OTHER INFORMATION: Any amino acid comprising a
small hydrophobic side chain or a polar/neutral side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (6)..(6) <223> OTHER INFORMATION: Any amino acid
comprising a large hydrophobic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Any amino acid comprising a large
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (8)..(8) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(10)..(10) <223> OTHER INFORMATION: Any amino acid comprising
a polar/neutral side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (11)..(11) <223>
OTHER INFORMATION: Any amino acid comprising a large hydrophobic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <400>
SEQUENCE: 1 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10
<210> SEQ ID NO 2 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 2 Leu Asp Leu Thr Tyr Asp
Glu Leu Leu Ala Cys Thr 1 5 10 <210> SEQ ID NO 3 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 3 Trp Ala Tyr Asp Trp Ser Cys Phe Arg Arg Arg Leu 1 5 10
<210> SEQ ID NO 4 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 4 Phe Leu His Trp Pro Val
Tyr Phe Cys Gln Val Met 1 5 10 <210> SEQ ID NO 5 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 5 Phe Leu Pro Trp Pro Val Tyr Phe Ser Gln Val Leu 1 5 10
<210> SEQ ID NO 6 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 6 Phe Val Glu Trp Gln Ala
Tyr Phe Ser Gln Met Met 1 5 10 <210> SEQ ID NO 7 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(1)..(1) <223> OTHER INFORMATION: Any amino acid comprising a
large hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(4)..(4) <223> OTHER INFORMATION: Any amino acid comprising a
large hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (5)..(5) <223> OTHER
INFORMATION: Any amino acid comprising an acidic side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (6)..(6) <223> OTHER INFORMATION: Any amino acid
comprising an acidic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (7)..(7) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(9)..(9) <223> OTHER INFORMATION: Any amino acid <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(10)..(10) <223> OTHER INFORMATION: Any amino acid comprising
a polar/neutral side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (11)..(11) <223>
OTHER INFORMATION: Any amino acid comprising a large hydrophobic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <400>
SEQUENCE: 7 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10
<210> SEQ ID NO 8
<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 8 Phe Ile Pro Trp Asp Glu Tyr Phe Ala Gln Leu
Leu 1 5 10 <210> SEQ ID NO 9 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 9 Phe
Ile Pro Trp Asp Glu Tyr Phe Lys Gln Val Leu 1 5 10 <210> SEQ
ID NO 10 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 10 Phe Val Pro Trp Asp Val Tyr Phe
Ser Gln Ile Leu 1 5 10 <210> SEQ ID NO 11 <211> LENGTH:
12 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 11 Phe
Ile Pro Trp Asp Glu Tyr Phe Lys Gln Val Leu 1 5 10 <210> SEQ
ID NO 12 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 12 Phe Val Pro Trp Pro Glu Tyr Phe
Leu Gln Ile Met 1 5 10 <210> SEQ ID NO 13 <211> LENGTH:
12 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 13 Phe
Ile Pro Trp Glu Glu Tyr Phe Ser Gln Leu Leu 1 5 10 <210> SEQ
ID NO 14 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 14 Phe Ile Pro Trp Pro Glu Tyr Phe
Ser Gln Leu Leu 1 5 10 <210> SEQ ID NO 15 <211> LENGTH:
12 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 15 Phe
Val Pro Trp Asp Glu Tyr Phe Leu Gln Ile Leu 1 5 10 <210> SEQ
ID NO 16 <211> LENGTH: 4 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (1)..(1) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Any amino acid <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(3)..(3) <223> OTHER INFORMATION: Any amino acid <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(4)..(4) <223> OTHER INFORMATION: Any amino acid comprising a
small hydrophobic side chain <400> SEQUENCE: 16 Xaa Xaa Xaa
Xaa 1 <210> SEQ ID NO 17 <211> LENGTH: 8 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (1)..(1) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (4)..(4) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (5)..(5) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(8)..(8) <223> OTHER INFORMATION: Any amino acid comprising a
basic side chain or a polar/neutral side chain <400>
SEQUENCE: 17 Xaa Cys Xaa Xaa Xaa Xaa Cys Xaa 1 5 <210> SEQ ID
NO 18 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (1)..(1) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Any amino acid comprising a
large hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (5)..(5) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(10)..(10) <223> OTHER INFORMATION: Any amino acid comprising
a basic side chain or a polar/neutral side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (11)..(11) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(12)..(12) <223> OTHER INFORMATION: Any amino acid
<400> SEQUENCE: 18 Xaa Xaa Xaa Cys Xaa Xaa Xaa Xaa Cys Xaa
Xaa Xaa 1 5 10 <210> SEQ ID NO 19 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 19 Phe
Val Leu Cys Gly Leu Gln Gly Cys Arg Gly Ser 1 5 10 <210> SEQ
ID NO 20 <211> LENGTH: 10 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 20 Lys Val Ile Cys Gly Trp Asp Gly
Cys Arg 1 5 10 <210> SEQ ID NO 21 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 21 Leu
Val Phe Cys Gly Lys Asn Gly Cys His Ser Gly 1 5 10 <210> SEQ
ID NO 22 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 22 Val Val Leu Cys Thr Pro Lys Gly
Cys Arg Ser Ala 1 5 10 <210> SEQ ID NO 23 <211> LENGTH:
12 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 23 Tyr
Val Met Cys Ser Ala Phe Gly Cys Lys Ser Ile 1 5 10 <210> SEQ
ID NO 24 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 24 Phe Val His Cys Thr Leu Leu Gly
Cys Trp Ser Gly 1 5 10 <210> SEQ ID NO 25 <211> LENGTH:
5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (1)..(1)
<223> OTHER INFORMATION: Any amino acid comprising a small
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(4)..(4) <223> OTHER INFORMATION: Any amino acid comprising a
small hydrophobic side chain <400> SEQUENCE: 25 Xaa Xaa Xaa
Xaa Cys 1 5 <210> SEQ ID NO 26 <211> LENGTH: 8
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (1)..(1)
<223> OTHER INFORMATION: Any amino acid comprising a large
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (4)..(4) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(5)..(5) <223> OTHER INFORMATION: Any amino acid comprising a
large hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (6)..(6) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Any
amino acid comprising a basic side chain <400> SEQUENCE: 26
Xaa Cys Xaa Xaa Xaa Xaa Cys Xaa 1 5 <210> SEQ ID NO 27
<211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (1)..(1) <223> OTHER INFORMATION: Any amino acid
comprising a large hydrophobic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Any amino acid comprising a large
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (4)..(4) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (5)..(5) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(6)..(6) <223> OTHER INFORMATION: Any amino acid comprising a
large hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (7)..(7) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Any
amino acid comprising a basic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (10)..(10)
<223> OTHER INFORMATION: Any amino acid comprising a small
hydrophobic side chain <400> SEQUENCE: 27
Xaa Xaa Cys Xaa Xaa Xaa Xaa Cys Xaa Xaa 1 5 10 <210> SEQ ID
NO 28 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (1)..(1) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Any amino acid comprising a
large hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (5)..(5) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(6)..(6) <223> OTHER INFORMATION: Any amino acid comprising a
small hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (7)..(7) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(10)..(10) <223> OTHER INFORMATION: Any amino acid comprising
a basic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (11)..(11) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <400>
SEQUENCE: 28 Xaa Xaa Xaa Cys Xaa Xaa Xaa Xaa Cys Xaa Xaa Xaa 1 5 10
<210> SEQ ID NO 29 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 29 Trp Val Ile Cys Ser Ala
Leu Gly Cys Arg Ser Leu 1 5 10 <210> SEQ ID NO 30 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 30 Trp Val Ile Cys Ser Ala Leu Gly Cys Arg Ser Met 1 5 10
<210> SEQ ID NO 31 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 31 Trp Val Ile Cys Ser Ala
Val Gly Cys Arg Pro Phe 1 5 10 <210> SEQ ID NO 32 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 32 Trp Val Ile Cys Ser Ala Met Gly Cys Arg Ser Ile 1 5 10
<210> SEQ ID NO 33 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 33 Trp Val Ile Cys Ser Ala
Leu Gly Cys Arg Ser Ile 1 5 10 <210> SEQ ID NO 34 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 34 Trp Val Ile Cys Ser Ala Phe Gly Cys Arg Ser Met 1 5 10
<210> SEQ ID NO 35 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 35 Trp Val Ile Cys Ser Ala
Leu Gly Cys Arg Pro Phe 1 5 10 <210> SEQ ID NO 36 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 36 Trp Val Ile Cys Ser Ala Leu Gly Cys Lys Ala Trp 1 5 10
<210> SEQ ID NO 37 <211> LENGTH: 5 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (1)..(1) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain or an acidic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (4)..(4) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (5)..(5) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <400> SEQUENCE: 37 Xaa Xaa Xaa Xaa Xaa 1 5 <210>
SEQ ID NO 38 <211> LENGTH: 9 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (1)..(1) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain or an acidic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (4)..(4) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (5)..(5) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(9)..(9) <223> OTHER INFORMATION: Any amino acid comprising a
basic side chain <400> SEQUENCE: 38 Xaa Cys Xaa Xaa Xaa Xaa
Xaa Cys Xaa 1 5 <210> SEQ ID NO 39 <211> LENGTH: 10
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (1)..(1)
<223> OTHER INFORMATION: Any amino acid comprising a large
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain or an acidic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (4)..(4) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (5)..(5) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (6)..(6) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (7)..(7) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Any
amino acid comprising a basic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (10)..(10)
<223> OTHER INFORMATION: Any amino acid <400> SEQUENCE:
39 Xaa Cys Xaa Xaa Xaa Xaa Xaa Cys Xaa Xaa 1 5 10 <210> SEQ
ID NO 40 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (1)..(1) <223> OTHER INFORMATION: Any
amino acid comprising an aromatic side chain or a large hydrophobic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(3)..(3) <223> OTHER INFORMATION: Any amino acid comprising a
large hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (5)..(5) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain or an acidic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (6)..(6) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (7)..(7) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (8)..(8) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (9)..(9) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (11)..(11) <223> OTHER INFORMATION: Any
amino acid comprising a basic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (12)..(12)
<223> OTHER INFORMATION: Any amino acid <400> SEQUENCE:
40 Xaa Xaa Xaa Cys Xaa Xaa Xaa Xaa Xaa Cys Xaa Xaa 1 5 10
<210> SEQ ID NO 41 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 41 Tyr Val Leu Cys Ser Asn
Arg Asn Gly Cys Arg Pro 1 5 10 <210> SEQ ID NO 42 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 42 Tyr Val Thr Cys Arg Trp Gly Tyr Gly Cys Thr Arg 1 5 10
<210> SEQ ID NO 43 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 43 Trp Val Ala Cys Ser Trp
Asp His Gly Cys Arg Ser 1 5 10 <210> SEQ ID NO 44 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 44 His Val Ile Cys Ser Val Asn Gly Gly Cys Arg Gly 1 5 10
<210> SEQ ID NO 45 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Any amino acid <400> SEQUENCE: 45 Trp Val Xaa
Cys Lys Pro Leu His Gly Cys Tyr Gly 1 5 10 <210> SEQ ID NO 46
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (1)..(1) <223> OTHER INFORMATION: Any amino acid
comprising a large hydrophobic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Any
amino acid comprising a basic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (3)..(3)
<223> OTHER INFORMATION: Any amino acid comprising a small
hydrophobic side chain or a polar neutral side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(4)..(4) <223> OTHER INFORMATION: Any amino acid comprising
an acidic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (5)..(5) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain <400>
SEQUENCE: 46 Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 <210> SEQ ID NO
47 <211> LENGTH: 11 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (1)..(1) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain or an aromatic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(4)..(4) <223> OTHER INFORMATION: Any amino acid comprising a
basic side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (5)..(5) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain or a polar
neutral side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (6)..(6) <223> OTHER
INFORMATION: Any amino acid comprising an acidic side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (7)..(7) <223> OTHER INFORMATION: Any amino acid
comprising a small hydrophobic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (8)..(8)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (9)..(9)
<223> OTHER INFORMATION: Any amino acid comprising a small
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (11)..(11) <223> OTHER
INFORMATION: Any amino acid comprising an aromatic side chain or a
large hydrophobic side chain <400> SEQUENCE: 47 Xaa Cys Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Cys Xaa 1 5 10 <210> SEQ ID NO 48
<211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (1)..(1) <223> OTHER INFORMATION: Any amino acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Any amino acid
comprising a large hydrophobic side chain or an aromatic side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (4)..(4) <223> OTHER INFORMATION: Any amino acid
comprising a large hydrophobic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (5)..(5)
<223> OTHER INFORMATION: Any amino acid comprising a basic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain or a polar
neutral side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (7)..(7) <223> OTHER
INFORMATION: Any amino acid comprising an acidic side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (8)..(8) <223> OTHER INFORMATION: Any amino acid
comprising a small hydrophobic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (9)..(9)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (10)..(10)
<223> OTHER INFORMATION: Any amino acid comprising a small
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Any amino acid comprising an aromatic side chain or a
large hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (13)..(13) <223>
OTHER INFORMATION: Any amino acid comprising a small hydrophobic
side chain or a polar neutral side chain <400> SEQUENCE: 48
Xaa Xaa Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Cys Xaa Xaa 1 5 10
<210> SEQ ID NO 49 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (1)..(1) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain or an aromatic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (5)..(5) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Any
amino acid comprising a basic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Any amino acid comprising a small
hydrophobic side chain or a polar neutral side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(8)..(8) <223> OTHER INFORMATION: Any amino acid comprising
an acidic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (9)..(9) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (11)..(11) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(13)..(13) <223> OTHER INFORMATION: Any amino acid comprising
an aromatic side chain or a large hydrophobic side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (14)..(14) <223> OTHER INFORMATION: Any amino acid
comprising a small hydrophobic side chain or a polar neutral side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (15)..(15) <223> OTHER INFORMATION: Any
amino acid
<400> SEQUENCE: 49 Xaa Xaa Xaa Cys Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Cys Xaa Xaa Xaa 1 5 10 15 <210> SEQ ID NO 50 <211>
LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 50 Glu Gln Phe Cys Leu Val Ser Asp Pro Met Ala Cys Trp
Ser Leu 1 5 10 15 <210> SEQ ID NO 51 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 51 Lys
Tyr Trp Cys Leu Arg Ser Glu Pro Asp Ala Cys Phe Ala Thr 1 5 10 15
<210> SEQ ID NO 52 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 52 Arg Val Tyr Cys Leu Ala
Ser Glu Pro Asn Ser Cys Trp Ser Thr 1 5 10 15 <210> SEQ ID NO
53 <211> LENGTH: 15 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 53 Thr Lys Leu Cys Leu Lys Ser Glu
Pro Gln Ala Cys Trp Ser Met 1 5 10 15 <210> SEQ ID NO 54
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 54 Ile Arg Phe Cys Leu Arg Ser Glu Pro Thr
Ala Cys Trp Ile Val 1 5 10 15 <210> SEQ ID NO 55 <211>
LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(1)..(1) <223> OTHER INFORMATION: Any amino acid comprising a
large hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Any amino acid comprising a basic side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Any amino acid
comprising a small hydrophobic side chain or a polar neutral side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (4)..(4) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(5)..(5) <223> OTHER INFORMATION: Any amino acid comprising a
small hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (6)..(6) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain or a polar neutral side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Any amino acid comprising a small
hydrophobic side chain <400> SEQUENCE: 55 Xaa Xaa Xaa Xaa Xaa
Xaa Xaa 1 5 <210> SEQ ID NO 56 <211> LENGTH: 11
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (1)..(1)
<223> OTHER INFORMATION: Any amino acid comprising a large
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (4)..(4) <223> OTHER INFORMATION: Any
amino acid comprising a basic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (5)..(5)
<223> OTHER INFORMATION: Any amino acid comprising a small
hydrophobic side chain or a polar neutral side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(6)..(6) <223> OTHER INFORMATION: Any amino acid comprising a
large hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (7)..(7) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain or a polar
neutral side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (9)..(9) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (11)..(11) <223> OTHER INFORMATION: Any
amino acid comprising an aromatic side chain or a large hydrophobic
side chain <400> SEQUENCE: 56 Xaa Cys Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Cys Xaa 1 5 10 <210> SEQ ID NO 57 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (1)..(1)
<223> OTHER INFORMATION: Any basic amino acid <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Any amino acid comprising a
large hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (4)..(4) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (5)..(5) <223> OTHER INFORMATION: Any
amino acid comprising a basic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (6)..(6)
<223> OTHER INFORMATION: Any amino acid comprising a small
hydrophobic side chain or a polar neutral side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(7)..(7) <223> OTHER INFORMATION: Any amino acid comprising a
large hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (8)..(8) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain or a polar
neutral side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (10)..(10) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Any
amino acid comprising an aromatic side chain or a large hydrophobic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain or a polar
neutral side chain <400> SEQUENCE: 57 Xaa Xaa Cys Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Cys Xaa Xaa 1 5 10 <210> SEQ ID NO 58
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (1)..(1) <223> OTHER INFORMATION: Any basic amino
acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Any basic amino
acid <220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Any amino acid
comprising a large hydrophobic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (5)..(5)
<223> OTHER INFORMATION: Any amino acid comprising a large
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (6)..(6) <223> OTHER
INFORMATION: Any amino acid comprising a basic side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (7)..(7) <223> OTHER INFORMATION: Any amino acid
comprising a small hydrophobic side chain or a polar neutral side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(9)..(9) <223> OTHER INFORMATION: Any amino acid comprising a
small hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Any amino acid comprising a small hydrophobic
side chain or a polar neutral side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (11)..(11)
<223> OTHER INFORMATION: Any amino acid comprising a small
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (13)..(13) <223> OTHER
INFORMATION: Any amino acid comprising an aromatic side chain or a
large hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (14)..(14) <223>
OTHER INFORMATION: Any amino acid comprising a small hydrophobic
side chain or a polar neutral side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (15)..(15)
<223> OTHER INFORMATION: Any amino acid comprising a large
hydrophobic side chain <400> SEQUENCE: 58 Xaa Xaa Xaa Cys Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Cys Xaa Xaa Xaa 1 5 10 15 <210> SEQ
ID NO 59 <211> LENGTH: 15 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 59 Arg Arg Phe Cys Leu Arg Ser Glu
Pro Thr Ala Cys Trp Ile Val 1 5 10 15 <210> SEQ ID NO 60
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 60 Lys Leu Phe Cys Leu Arg Ser Gly Asp Arg
Ala Cys Trp Val Val 1 5 10 15 <210> SEQ ID NO 61 <211>
LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 61 Met Arg Phe Cys Leu Arg Ser Glu Pro Thr Ala Cys Trp
Thr Val 1 5 10 15 <210> SEQ ID NO 62 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 62 Arg
Arg Phe Cys Leu Arg Ser Glu Pro Thr Ala Cys Trp Asp Val 1 5 10 15
<210> SEQ ID NO 63 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 63 Arg Arg Phe Cys Leu Arg
Ser Asp Pro Thr Ala Cys Trp Ile Val 1 5 10 15 <210> SEQ ID NO
64 <211> LENGTH: 15 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 64 Lys Arg Phe Cys Leu Arg Ser Glu
Pro Thr Ala Cys Trp Thr Val 1 5 10 15 <210> SEQ ID NO 65
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 65 Arg Arg Phe Cys Leu Arg Ser Glu Pro Met
Ala Cys Trp Thr Val 1 5 10 15 <210> SEQ ID NO 66 <211>
LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 66 Arg Arg Phe Cys Leu Arg Ser Glu Pro Thr Ala Cys Trp
Thr Val 1 5 10 15 <210> SEQ ID NO 67 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 67 Arg
Arg Phe Cys Leu Arg Ser Glu Pro Ala Ala Cys Trp Phe Val 1 5 10
15
<210> SEQ ID NO 68 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 68 Arg Arg Phe Cys Leu Arg
Ser Glu Pro Thr Ala Cys Trp Tyr Val 1 5 10 15 <210> SEQ ID NO
69 <211> LENGTH: 8 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (1)..(1) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain or a basic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Any
amino acid comprising an acidic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (4)..(4)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (5)..(5)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (6)..(6)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Any amino acid comprising a small
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (8)..(8) <223> OTHER
INFORMATION: Any amino acid <400> SEQUENCE: 69 Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa 1 5 <210> SEQ ID NO 70 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(1)..(1) <223> OTHER INFORMATION: Any amino acid comprising a
basic side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain or a basic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (4)..(4) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (5)..(5) <223> OTHER INFORMATION: Any
amino acid comprising an acidic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (6)..(6)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (8)..(8)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (9)..(9)
<223> OTHER INFORMATION: Any amino acid comprising a small
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (10)..(10) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (12)..(12) <223>
OTHER INFORMATION: Any amino acid comprising a large hydrophobic
side chain <400> SEQUENCE: 70 Xaa Cys Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Cys Xaa 1 5 10 <210> SEQ ID NO 71 <211> LENGTH:
14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (1)..(1)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Any amino acid comprising a basic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (4)..(4) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain or a basic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (5)..(5) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Any
amino acid comprising an acidic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (8)..(8)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (9)..(9)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (10)..(10)
<223> OTHER INFORMATION: Any amino acid comprising a small
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (11)..(11) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (13)..(13) <223>
OTHER INFORMATION: Any amino acid comprising a large hydrophobic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (14)..(14) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <400>
SEQUENCE: 71 Xaa Xaa Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Cys Xaa
Xaa 1 5 10 <210> SEQ ID NO 72 <211> LENGTH: 14
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 72 Arg
Ser Cys Asn Arg Tyr Gly Ile Trp Gly His Cys Asp Thr 1 5 10
<210> SEQ ID NO 73 <211> LENGTH: 14 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 73 Ile Lys Cys Arg Val Leu
Glu Ala Gly Thr Pro Cys Val Phe 1 5 10 <210> SEQ ID NO 74
<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 74 Ile Arg Cys Arg Tyr Glu Lys Gln Ser Gly
Ile Cys Leu Phe 1 5 10 <210> SEQ ID NO 75
<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 75 Leu Arg Cys Arg Leu Asp Thr Arg Asp Gly
Thr Cys Arg Phe 1 5 10 <210> SEQ ID NO 76 <211> LENGTH:
14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 76 Met
Arg Cys Ile Leu Ser Pro Ser Arg Glu His Cys Leu Phe 1 5 10
<210> SEQ ID NO 77 <211> LENGTH: 14 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 77 Asn His Cys Thr Met Asp
Trp Arg Leu Gly Ala Cys Ile Phe 1 5 10 <210> SEQ ID NO 78
<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 78 Ser Gly Cys Arg Leu Ser Leu Leu Asp Gly
His Cys Tyr Phe 1 5 10 <210> SEQ ID NO 79 <211> LENGTH:
14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 79 Ser
Lys Cys Val Tyr Asp Tyr Asn Phe Gly Thr Cys Ile Phe 1 5 10
<210> SEQ ID NO 80 <211> LENGTH: 14 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 80 Ser Arg Cys Val Met Ser
Leu Gln Leu Gly Ala Cys Ile Phe 1 5 10 <210> SEQ ID NO 81
<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 81 Thr Arg Cys Thr Val Ile Gly Pro Pro Trp
Ser Cys Arg Phe 1 5 10 <210> SEQ ID NO 82 <211> LENGTH:
14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 82 Val
Phe Cys Ile Gly Tyr Gly Ala Ala Gln Ser Cys His Ser 1 5 10
<210> SEQ ID NO 83 <211> LENGTH: 14 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 83 Val Arg Cys Leu Tyr Asp
Ser Ile Thr Arg Thr Cys Thr Phe 1 5 10 <210> SEQ ID NO 84
<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 84 Val Ser Cys Lys Ile Asp Arg Arg Ser Gly
Ser Cys Leu Phe 1 5 10 <210> SEQ ID NO 85 <211> LENGTH:
14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 85 Val
Ser Cys Arg Phe Arg Pro Asp Leu Gly Phe Cys Ile Phe 1 5 10
<210> SEQ ID NO 86 <211> LENGTH: 14 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 86 Asp Arg Cys Asp Thr Arg
Thr Trp Gly Tyr Tyr Cys Trp Ile 1 5 10 <210> SEQ ID NO 87
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (1)..(1) <223> OTHER INFORMATION: Any amino acid
comprising a large hydrophobic side chain or a basic side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Any amino acid
comprising a large hydrophobic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (3)..(3)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (4)..(4)
<223> OTHER INFORMATION: Any amino acid comprising a small
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (5)..(5) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain or a basic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Any
amino acid comprising a basic side chain or an acidic side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (8)..(8) <223> OTHER INFORMATION: Any amino acid
comprising a small hydrophobic side chain or a polar neutral side
chain <400> SEQUENCE: 87 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5
<210> SEQ ID NO 88 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <220> FEATURE: <221> NAME/KEY:
MOD_RES
<222> LOCATION: (1)..(1) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain or an acidic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain or a basic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (4)..(4) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(5)..(5) <223> OTHER INFORMATION: Any amino acid <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(6)..(6) <223> OTHER INFORMATION: Any amino acid comprising a
small hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (7)..(7) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain or a basic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Any
amino acid comprising a basic side chain or an acidic side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Any amino acid
comprising a small hydrophobic side chain or a polar neutral side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Any
amino acid <400> SEQUENCE: 88 Xaa Cys Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Cys Xaa 1 5 10 <210> SEQ ID NO 89 <211> LENGTH:
14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (1)..(1)
<223> OTHER INFORMATION: Any amino acid comprising a large
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain or an acidic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (4)..(4) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain or a basic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (5)..(5) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(8)..(8) <223> OTHER INFORMATION: Any amino acid comprising a
small hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (9)..(9) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain or a basic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Any amino acid comprising a basic side chain or
an acidic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (11)..(11) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain or a polar neutral side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (13)..(13)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (14)..(14)
<223> OTHER INFORMATION: Any amino acid <400> SEQUENCE:
89 Xaa Xaa Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Cys Xaa Xaa 1 5 10
<210> SEQ ID NO 90 <211> LENGTH: 16 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (1)..(1) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain or an acidic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (5)..(5) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain or a basic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(7)..(7) <223> OTHER INFORMATION: Any amino acid <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(8)..(8) <223> OTHER INFORMATION: Any amino acid comprising a
small hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (9)..(9) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain or a basic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (11)..(11) <223> OTHER INFORMATION: Any
amino acid comprising a basic side chain or an acidic side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (12)..(12) <223> OTHER INFORMATION: Any amino acid
comprising a small hydrophobic side chain or a polar neutral side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (14)..(14) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (15)..(15) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (16)..(16) <223> OTHER INFORMATION: Any
amino acid <400> SEQUENCE: 90 Xaa Xaa Xaa Cys Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Cys Xaa Xaa Xaa 1 5 10 15 <210> SEQ ID NO 91
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 91 Gly Ser Arg Cys Tyr Trp Asp Pro Gly Arg
Glu Val Cys Ile Phe Lys 1 5 10 15 <210> SEQ ID NO 92
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 92 Glu Trp Glu Cys Arg Phe
Leu Pro Gly Arg Arg Gly Cys Ser Leu Phe 1 5 10 15 <210> SEQ
ID NO 93 <211> LENGTH: 16 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 93 Phe Trp Glu Cys Val Tyr Ser Pro
Gly Ser Arg Gly Cys Arg Met Val 1 5 10 15 <210> SEQ ID NO 94
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 94 Gly Phe Arg Cys Thr Tyr Asp Pro Gly Thr
His Ser Cys Trp Ser Ile 1 5 10 15 <210> SEQ ID NO 95
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 95 Lys Trp Ile Cys Arg Leu Val Pro Gly Asn
Gly Ala Cys His Ser Phe 1 5 10 15 <210> SEQ ID NO 96
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 96 Pro Trp Val Cys Glu His Tyr Pro Gly Arg
Arg Gly Cys Val Leu Met 1 5 10 15 <210> SEQ ID NO 97
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 97 Gln Trp Ser Cys Val Phe Ser Pro Gly Val
Arg Gly Cys Lys Leu Val 1 5 10 15 <210> SEQ ID NO 98
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 98 Arg Phe Ile Cys Arg Ile Gln Pro Gly Arg
Glu Gly Cys Trp Ser Leu 1 5 10 15 <210> SEQ ID NO 99
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 99 Arg Trp Glu Cys Ile Tyr Ile Pro Gly Arg
Lys Gly Cys Thr Leu Gln 1 5 10 15 <210> SEQ ID NO 100
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 100 Ser Leu Asn Cys Lys Thr Arg Pro Gly Leu
Arg Trp Cys Thr Trp Thr 1 5 10 15 <210> SEQ ID NO 101
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 101 Ser Trp Glu Cys Val Tyr Met Pro Gly His
Gln Gly Cys Arg Leu Phe 1 5 10 15 <210> SEQ ID NO 102
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 102 Val Arg Phe Cys Arg Ser Gly Pro Gly Trp
Val Ser Cys Gly Thr Gln 1 5 10 15 <210> SEQ ID NO 103
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 103 Val Arg Leu Cys Arg Val Gly Pro Gly Tyr
Glu Ser Cys Pro Ala Asn 1 5 10 15 <210> SEQ ID NO 104
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 104 Val Arg Met Cys Tyr Val Ala Pro Gly Tyr
Val Ser Cys Pro Arg Met 1 5 10 15 <210> SEQ ID NO 105
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (1)..(1) <223> OTHER INFORMATION: Any amino acid
comprising a large hydrophobic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Any amino acid comprising a large
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (4)..(4) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(5)..(5) <223> OTHER INFORMATION: Any amino acid comprising a
small hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (6)..(6) <223> OTHER
INFORMATION: Any amino acid comprising a basic side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (7)..(7) <223> OTHER INFORMATION: Any amino acid
comprising a basic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (8)..(8) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <400> SEQUENCE: 105 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1
5
<210> SEQ ID NO 106 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (1)..(1) <223> OTHER
INFORMATION: Any amino acid comprising an acidic side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Any amino acid
comprising a large hydrophobic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (4)..(4)
<223> OTHER INFORMATION: Any amino acid comprising a large
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (5)..(5) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(7)..(7) <223> OTHER INFORMATION: Any amino acid comprising a
small hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (8)..(8) <223> OTHER
INFORMATION: Any amino acid comprising a basic side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (9)..(9) <223> OTHER INFORMATION: Any amino acid
comprising a basic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Any amino acid comprising a small hydrophobic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain or a polar
neutral side chain <400> SEQUENCE: 106 Xaa Cys Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Cys Xaa 1 5 10 <210> SEQ ID NO 107
<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (1)..(1) <223> OTHER INFORMATION: Any amino acid
comprising a large hydrophobic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Any amino acid comprising an acidic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (4)..(4) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(5)..(5) <223> OTHER INFORMATION: Any amino acid comprising a
large hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (6)..(6) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(8)..(8) <223> OTHER INFORMATION: Any amino acid comprising a
small hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (9)..(9) <223> OTHER
INFORMATION: Any amino acid comprising a basic side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Any amino acid
comprising a basic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (11)..(11) <223>
OTHER INFORMATION: Any amino acid comprising a small hydrophobic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain or a polar
neutral side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (14)..(14) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <400> SEQUENCE: 107 Xaa Xaa Cys Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Cys Xaa Xaa 1 5 10 <210> SEQ ID NO 108 <211>
LENGTH: 16 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(1)..(1) <223> OTHER INFORMATION: Any amino acid comprising
an acidic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Any
amino acid comprising an acidic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (5)..(5)
<223> OTHER INFORMATION: Any amino acid comprising a large
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (6)..(6) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(8)..(8) <223> OTHER INFORMATION: Any amino acid comprising a
small hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (9)..(9) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Any
amino acid comprising a basic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (11)..(11)
<223> OTHER INFORMATION: Any amino acid comprising a basic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(14)..(14) <223> OTHER INFORMATION: Any amino acid comprising
a small hydrophobic side chain or a polar neutral side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (15)..(15) <223> OTHER INFORMATION: Any amino acid
comprising a large hydrophobic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (16)..(16)
<223> OTHER INFORMATION: Any amino acid comprising a large
hydrophobic side chain <400> SEQUENCE: 108 Xaa Xaa Xaa Cys
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Cys Xaa Xaa Xaa 1 5 10 15
<210> SEQ ID NO 109 <211> LENGTH: 16 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 109 Asn Trp Glu Cys Ile Phe
Ser Pro Gly Arg Arg Gly Cys Ser Leu Thr 1 5 10 15 <210> SEQ
ID NO 110 <211> LENGTH: 16 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 110 Asp Trp Glu Cys Leu Phe Leu Pro
Gly Arg Arg Gly Cys Leu Leu Phe 1 5 10 15 <210> SEQ ID NO 111
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 111 Glu Trp Glu Cys Leu Phe Met Pro Gly Arg
Arg Gly Cys Leu Leu Met 1 5 10 15 <210> SEQ ID NO 112
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 112 Ala Trp Glu Cys Leu Phe Leu Pro Gly His
Arg Gly Cys Ser Leu Phe 1 5 10 15 <210> SEQ ID NO 113
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 113 Glu Trp Glu Cys Leu Phe Leu Pro Gly Arg
Lys Gly Cys Thr Leu Phe 1 5 10 15 <210> SEQ ID NO 114
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 114 Asp Trp Glu Cys Ile Phe Leu Pro Gly Arg
Arg Gly Cys Thr Leu Phe 1 5 10 15 <210> SEQ ID NO 115
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 115 Val Tyr Glu Cys Leu Phe Met Pro Gly Arg
Lys Gly Cys Phe Gly Met 1 5 10 15 <210> SEQ ID NO 116
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 116 Glu Trp Glu Cys Trp Phe Leu Pro Gly Arg
Arg Gly Cys Thr Leu Ile 1 5 10 15 <210> SEQ ID NO 117
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 117 Asp Trp His Cys Leu Phe Leu Pro Gly His
Arg Gly Cys Thr Leu Phe 1 5 10 15 <210> SEQ ID NO 118
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 118 Asp Trp Glu Cys Leu Phe Leu Pro Gly Arg
Arg Gly Cys Thr Leu Phe 1 5 10 15 <210> SEQ ID NO 119
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 119 Tyr Trp Glu Cys Val Phe Met Pro Gly His
Arg Gly Cys Ser Leu Ile 1 5 10 15 <210> SEQ ID NO 120
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 120 Thr Trp Asp Cys Leu Phe Leu Pro Gly Arg
Arg Gly Cys Thr Leu Met 1 5 10 15 <210> SEQ ID NO 121
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 121 Asn Trp Glu Cys Ile Phe Ser Pro Gly Arg
Arg Gly Cys Ser Leu Thr 1 5 10 15 <210> SEQ ID NO 122
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (1)..(1) <223> OTHER INFORMATION: Any amino acid
comprising an acidic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Any amino acid comprising an acidic side chain or an
aromatic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (4)..(4) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (5)..(5) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(6)..(6) <223> OTHER INFORMATION: Any amino acid comprising
an aromatic chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (7)..(7) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (8)..(8) <223> OTHER
INFORMATION: Any amino acid <400> SEQUENCE: 122 Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa 1 5 <210> SEQ ID NO 123
<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (1)..(1) <223> OTHER INFORMATION: Any amino acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Any amino acid
comprising an acidic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (4)..(4) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (5)..(5) <223> OTHER
INFORMATION: Any amino acid comprising an acidic side chain or an
aromatic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (6)..(6) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(8)..(8) <223> OTHER INFORMATION: Any amino acid comprising
an aromatic chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (9)..(9) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (12)..(12) <223>
OTHER INFORMATION: Any amino acid <400> SEQUENCE: 123 Xaa Cys
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Cys Xaa 1 5 10 <210> SEQ ID
NO 124 <211> LENGTH: 14 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (1)..(1) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (4)..(4) <223> OTHER INFORMATION: Any
amino acid comprising an acidic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (5)..(5)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (6)..(6)
<223> OTHER INFORMATION: Any amino acid comprising an acidic
side chain or an aromatic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Any amino acid comprising a small
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (8)..(8) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Any
amino acid comprising an aromatic chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (10)..(10)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (11)..(11)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (13)..(13)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (14)..(14)
<223> OTHER INFORMATION: Any amino acid comprising a large
hydrophobic side chain <400> SEQUENCE: 124 Xaa Xaa Cys Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Cys Xaa Xaa 1 5 10 <210> SEQ ID
NO 125 <211> LENGTH: 16 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (1)..(1) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (5)..(5) <223> OTHER INFORMATION: Any
amino acid comprising an acidic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (6)..(6)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Any amino acid comprising an acidic
side chain or an aromatic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (8)..(8)
<223> OTHER INFORMATION: Any amino acid comprising a small
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (9)..(9) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Any
amino acid comprising an aromatic chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (11)..(11)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (12)..(12)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (14)..(14)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (15)..(15)
<223> OTHER INFORMATION: Any amino acid comprising a large
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (16)..(16) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <400> SEQUENCE: 125 Xaa Xaa Xaa Cys Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Cys Xaa Xaa Xaa 1 5 10 15 <210> SEQ ID NO 126
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 126 Ala Gly Trp Cys Lys Leu Asn Pro Gly Thr
Gln Val Cys Ser Phe Tyr 1 5 10 15 <210> SEQ ID NO 127
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 127 Glu Thr Pro Cys Asp Leu His Pro Gly His
Trp Ser Cys Ser Met Val 1 5 10 15 <210> SEQ ID NO 128
<211> LENGTH: 16 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 128 Phe Phe Leu Cys Asp Asp
Phe Pro Gly Leu Pro Arg Cys Glu Trp Ile 1 5 10 15 <210> SEQ
ID NO 129 <211> LENGTH: 16 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 129 Gly Leu Arg Cys Tyr Phe Asp Pro
Gly Ser Gln Ile Cys Thr Phe Leu 1 5 10 15 <210> SEQ ID NO 130
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 130 Gly Gln Arg Cys Thr Tyr Asp Pro Gly Gln
Asp Ala Cys Val Phe Ser 1 5 10 15 <210> SEQ ID NO 131
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 131 Gly Ser Arg Cys Tyr Trp Asp Pro Gly Arg
Glu Val Cys Ile Phe Lys 1 5 10 15 <210> SEQ ID NO 132
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 132 Lys Leu Trp Cys Gln Asn Asn Pro Gly Asn
Ser Ile Cys Asp Met Tyr 1 5 10 15 <210> SEQ ID NO 133
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 133 Lys Ser Trp Cys Phe Asp His Pro Gly Tyr
Pro Ile Cys Gln Phe Tyr 1 5 10 15 <210> SEQ ID NO 134
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 134 Arg Leu Phe Cys Leu Met Asn Pro Gly Pro
Pro Asp Cys Trp Ile Tyr 1 5 10 15 <210> SEQ ID NO 135
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 135 Arg Gln Phe Cys Leu Val Ser Pro Gly Tyr
Glu Asp Cys Trp Phe Val 1 5 10 15 <210> SEQ ID NO 136
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 136 Thr Arg Met Cys Phe Asp Asp Pro Gly Trp
His Ser Cys Pro Val Val 1 5 10 15 <210> SEQ ID NO 137
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 137 Thr Arg Trp Cys Ser Leu His Pro Gly Val
Gly Glu Cys Val Thr Leu 1 5 10 15 <210> SEQ ID NO 138
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 138 Thr Thr Val Cys Asp Tyr His Pro Gly Ser
Arg Tyr Cys Ile Asn Glu 1 5 10 15 <210> SEQ ID NO 139
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 139 Tyr Ala Ser Cys Thr Tyr Leu Pro Gly His
Arg Gly Cys Thr Leu Val 1 5 10 15 <210> SEQ ID NO 140
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 140 Trp Leu Pro Cys Asp Asp Tyr Pro Gly His
Gly Tyr Cys Tyr Ser Arg 1 5 10 15 <210> SEQ ID NO 141
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (1)..(1) <223> OTHER INFORMATION: Any amino acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Any amino acid
comprising a large hydrophobic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (3)..(3)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (4)..(4)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (5)..(5)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (6)..(6)
<223> OTHER INFORMATION: Any amino acid comprising an acidic
side chain, a small hydrophobic side chain, or a polar neutral side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(9)..(9) <223> OTHER INFORMATION: Any amino acid comprising a
large hydrophobic side chain <400> SEQUENCE: 141 Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa 1 5
<210> SEQ ID NO 142 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (1)..(1) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (4)..(4) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (5)..(5) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Any
amino acid comprising an acidic side chain, a small hydrophobic
side chain, or a polar neutral side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (9)..(9)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (10)..(10)
<223> OTHER INFORMATION: Any amino acid comprising a large
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (11)..(11) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <400>
SEQUENCE: 142 Xaa Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Cys Xaa 1
5 10 <210> SEQ ID NO 143 <211> LENGTH: 16 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (1)..(1) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (4)..(4) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (5)..(5) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Any
amino acid comprising an acidic side chain, a small hydrophobic
side chain, or a polar neutral side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (10)..(10)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (11)..(11)
<223> OTHER INFORMATION: Any amino acid comprising a large
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (12)..(12) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (14)..(14) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(15)..(15) <223> OTHER INFORMATION: Any amino acid comprising
a large hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (16)..(16) <223>
OTHER INFORMATION: Any amino acid <400> SEQUENCE: 143 Xaa Xaa
Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Cys Xaa Xaa Xaa 1 5 10 15
<210> SEQ ID NO 144 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 144 Ser Ala Cys Gln Leu Lys
Trp Asp Glu Gly Trp Thr Cys Leu Phe 1 5 10 15 <210> SEQ ID NO
145 <211> LENGTH: 15 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 145 Asn His Cys Thr Leu Ser Lys Thr
Tyr Pro Trp Val Cys Val Phe 1 5 10 15 <210> SEQ ID NO 146
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 146 Gln Arg Cys Asn Arg Ser Leu Leu Asp Ala
Leu Ile Cys Gln Ala 1 5 10 15 <210> SEQ ID NO 147 <211>
LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 147 Arg Gly Cys Met Leu Arg Leu Gln Pro Glu Leu Ala Cys
Val Phe 1 5 10 15 <210> SEQ ID NO 148 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 148
Gly Gly Cys Ser Leu Val Trp Ala Asp Ser Trp Val Cys Ile Phe 1 5 10
15 <210> SEQ ID NO 149 <211> LENGTH: 9 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (1)..(1) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(3)..(3) <223> OTHER INFORMATION: Any amino acid comprising a
large
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (4)..(4) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (5)..(5) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Any
amino acid comprising an acidic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Any amino acid comprising a small
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (8)..(8) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain or an acidic
side chain <400> SEQUENCE: 149 Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa 1 5 <210> SEQ ID NO 150 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (1)..(1)
<223> OTHER INFORMATION: Any amino acid comprising a small
hydrophobic side chain or a basic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (3)..(3)
<223> OTHER INFORMATION: Any amino acid comprising a small
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (4)..(4) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (5)..(5) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(6)..(6) <223> OTHER INFORMATION: Any amino acid comprising a
large hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (7)..(7) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (8)..(8) <223> OTHER
INFORMATION: Any amino acid comprising an acidic side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (9)..(9) <223> OTHER INFORMATION: Any amino acid
comprising a small hydrophobic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (10)..(10)
<223> OTHER INFORMATION: Any amino acid comprising a large
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (11)..(11) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain or an acidic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (13)..(13) <223>
OTHER INFORMATION: Any amino acid comprising a large hydrophobic
side chain <400> SEQUENCE: 150 Xaa Cys Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Cys Xaa 1 5 10 <210> SEQ ID NO 151
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (1)..(1) <223> OTHER INFORMATION: Any amino acid
comprising a small hydrophobic side chain or a basic side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Any amino acid
comprising a small hydrophobic side chain or a basic side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (4)..(4) <223> OTHER INFORMATION: Any amino acid
comprising a small hydrophobic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (5)..(5)
<223> OTHER INFORMATION: Any amino acid comprising a large
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (6)..(6) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(8)..(8) <223> OTHER INFORMATION: Any amino acid <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(9)..(9) <223> OTHER INFORMATION: Any amino acid comprising
an acidic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (10)..(10) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (11)..(11) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(12)..(12) <223> OTHER INFORMATION: Any amino acid comprising
a large hydrophobic side chain or an acidic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(14)..(14) <223> OTHER INFORMATION: Any amino acid comprising
a large hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (15)..(15) <223>
OTHER INFORMATION: Any amino acid comprising a large hydrophobic
side chain <400> SEQUENCE: 151 Xaa Xaa Cys Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Cys Xaa Xaa 1 5 10 15 <210> SEQ ID NO 152
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 152 Ser Arg Cys Ser Leu Val Trp Thr Asp Thr
Trp Val Cys Val Phe 1 5 10 15 <210> SEQ ID NO 153 <211>
LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 153 Ser Arg Cys Thr Leu Val Phe Asp Asp Ser Trp Val Cys
Val Phe 1 5 10 15 <210> SEQ ID NO 154 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE:
154
Arg Gly Cys Ser Leu Val Trp Ser Gly Ser Trp Glu Cys Ile Phe 1 5 10
15 <210> SEQ ID NO 155 <211> LENGTH: 15 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 155 Gln Ala Cys
Gln Leu Val Trp Leu Asp Ser Trp Val Cys Ile Phe 1 5 10 15
<210> SEQ ID NO 156 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 156 Val Gly Cys Ser Leu Val
Trp Thr Asp Arg Trp Glu Cys Ile Phe 1 5 10 15 <210> SEQ ID NO
157 <211> LENGTH: 15 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 157 Ser Gly Cys Ser Leu Gln Trp Ala
Asp Gly Trp Val Cys Ile Phe 1 5 10 15 <210> SEQ ID NO 158
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 158 Ala Arg Cys Ser Leu Val Trp Asp Glu Ala
Trp Val Cys Ile Phe 1 5 10 15 <210> SEQ ID NO 159 <211>
LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 159 Arg Gly Cys Ser Leu Val Trp Ala Gly Ser Trp Glu Cys
Ile Phe 1 5 10 15 <210> SEQ ID NO 160 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 160
Ser Arg Cys Ser Leu Val Trp Ala Glu Asn Trp Val Cys Ile Phe 1 5 10
15 <210> SEQ ID NO 161 <211> LENGTH: 15 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 161 Arg Arg Cys
Thr Leu Val Phe Leu Asp Ser Trp Glu Cys Ile Phe 1 5 10 15
<210> SEQ ID NO 162 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 162 Arg Gly Cys Thr Leu Ala
Trp Glu Asp Ser Trp Val Cys Ile Phe 1 5 10 15 <210> SEQ ID NO
163 <211> LENGTH: 15 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 163 Arg Gly Cys Ser Leu Arg Phe Ala
Glu Ala Trp Glu Cys Ile Phe 1 5 10 15 <210> SEQ ID NO 164
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 164 Ala Ser Cys Ser Leu Val Trp Gln Asp Ser
Trp Val Cys Ile Phe 1 5 10 15 <210> SEQ ID NO 165 <211>
LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 165 Ser Arg Cys Ser Leu Val Trp Ala Asp Ser Trp Val Cys
Ile Phe 1 5 10 15 <210> SEQ ID NO 166 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 166
Gly Arg Cys His Leu Val Trp Ser Asp Arg Trp Glu Cys Ile Phe 1 5 10
15 <210> SEQ ID NO 167 <211> LENGTH: 10 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (1)..(1) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(3)..(3) <223> OTHER INFORMATION: Any amino acid <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(4)..(4) <223> OTHER INFORMATION: Any amino acid comprising a
large hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (5)..(5) <223> OTHER
INFORMATION: Any amino acid comprising an acidic side chain or a
polar neutral side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (6)..(6) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (7)..(7) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (8)..(8) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(10)..(10) <223> OTHER INFORMATION: Any amino acid comprising
a large hydrophobic side chain or an acidic side chain <400>
SEQUENCE: 167 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10
<210> SEQ ID NO 168 <211> LENGTH: 14 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (1)..(1) <223> OTHER
INFORMATION: Any amino acid comprising a small hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(4)..(4) <223> OTHER INFORMATION: Any amino acid comprising a
large hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (5)..(5) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (6)..(6) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Any
amino acid comprising an acidic side chain or a polar neutral side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(11)..(11) <223> OTHER INFORMATION: Any amino acid comprising
a large hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (12)..(12) <223>
OTHER INFORMATION: Any amino acid comprising a large hydrophobic
side chain or an acidic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (14)..(14) <223>
OTHER INFORMATION: Any amino acid comprising a large hydrophobic
side chain <400> SEQUENCE: 168 Xaa Cys Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Cys Xaa 1 5 10 <210> SEQ ID NO 169
<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 169 Gly Cys Thr Leu Lys Trp Glu Ser Pro Asn
Trp Thr Cys Tyr 1 5 10 <210> SEQ ID NO 170 <211>
LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 170 Ser Cys Thr Val Arg Trp Asp Gly Asp Trp Trp Val Cys
Glu 1 5 10 <210> SEQ ID NO 171 <211> LENGTH: 14
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 171
Gly Cys Ser Leu Met Trp Gln Asp Gly Trp Trp Val Cys Ile 1 5 10
<210> SEQ ID NO 172 <211> LENGTH: 14 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 172 Gly Cys Thr Leu Ser Trp
Asn Gln Gly Trp Trp His Cys Val 1 5 10 <210> SEQ ID NO 173
<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 173 Gly Cys Met Leu Thr Arg Gly Lys Phe Trp
Trp Glu Cys Ile 1 5 10 <210> SEQ ID NO 174 <211>
LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 174 Gly Cys Val Leu Gln Phe Ser Gly Val Trp Trp Glu Cys
Val 1 5 10 <210> SEQ ID NO 175 <211> LENGTH: 10
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (1)..(1)
<223> OTHER INFORMATION: Any amino acid comprising a
polar/neutral side chain or a basic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Any amino acid comprising a large
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (4)..(4) <223> OTHER
INFORMATION: Any amino acid comprising a polar neutral side chain
or a basic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (7)..(7) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (8)..(8) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (9)..(9) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Any
amino acid comprising an acidic side chain or a polar/neutral side
chain <400> SEQUENCE: 175 Xaa Xaa Xaa Xaa Pro Gly Xaa Xaa Xaa
Xaa 1 5 10 <210> SEQ ID NO 176 <211> LENGTH: 14
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (1)..(1)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (3)..(3)
<223> OTHER INFORMATION: Any amino acid comprising a
polar/neutral side chain or a basic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (4)..(4)
<223> OTHER INFORMATION: Any amino acid comprising a large
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (5)..(5) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (6)..(6) <223> OTHER
INFORMATION: Any amino acid comprising a polar neutral side chain
or a basic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (9)..(9) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (11)..(11) <223>
OTHER INFORMATION: Any amino acid comprising a large hydrophobic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Any
amino acid comprising an acidic side chain or a polar/neutral side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (14)..(14) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <400>
SEQUENCE: 176 Xaa Cys Xaa Xaa Xaa Xaa Pro Gly Xaa Xaa Xaa Xaa Cys
Xaa 1 5 10 <210> SEQ ID NO 177 <211> LENGTH: 16
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (1)..(1)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (4)..(4)
<223> OTHER INFORMATION: Any amino acid comprising a
polar/neutral side chain or a basic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (5)..(5)
<223> OTHER INFORMATION: Any amino acid comprising a large
hydrophobic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (6)..(6) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (7)..(7) <223> OTHER
INFORMATION: Any amino acid comprising a polar neutral side chain
or a basic side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (10)..(10) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (11)..(11) <223>
OTHER INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (12)..(12) <223>
OTHER INFORMATION: Any amino acid comprising a large hydrophobic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Any
amino acid comprising an acidic side chain or a polar/neutral side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (15)..(15) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(16)..(16) <223> OTHER INFORMATION: Any amino acid comprising
a large hydrophobic side chain <400> SEQUENCE: 177 Xaa Xaa
Cys Xaa Xaa Xaa Xaa Pro Gly Xaa Xaa Xaa Xaa Cys Xaa Xaa 1 5 10 15
<210> SEQ ID NO 178 <211> LENGTH: 16 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 178 Gln Arg Cys Gln Leu Ser
Trp Ser Gly Gly Glu Leu Gly Cys Met Phe 1 5 10 15 <210> SEQ
ID NO 179 <211> LENGTH: 16 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 179 Ala Gly Cys Met Leu Leu Lys Pro
Gly Leu Tyr Trp Glu Cys Ile Phe 1 5 10 15 <210> SEQ ID NO 180
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 180 Ala Arg Cys Ser Leu His His Thr Gly Ser
Arg Tyr Glu Cys Ile Phe 1 5 10 15 <210> SEQ ID NO 181
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 181 Ala Thr Cys Met Leu Arg Leu Leu Gly Asp
Gly Trp Gly Cys Val Phe 1 5 10 15 <210> SEQ ID NO 182
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 182 Gly Pro Cys Arg Leu Ser Asn Pro Gly Thr
Gly Trp Glu Cys Ile Phe 1 5 10 15 <210> SEQ ID NO 183
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 183 Lys Gly Cys Thr Leu Gln Asn Pro Gly Ser
Gly Trp Val Cys Leu Phe 1 5 10 15 <210> SEQ ID NO 184
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 184 Leu Ala Cys Ile Leu Ser Lys Pro Gly Glu
His Trp Glu Cys Leu Phe 1 5 10 15 <210> SEQ ID NO 185
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 185 Asn Gly Cys Thr Leu Ser Phe Ser Gly Met
Ser Trp Thr Cys Val Tyr 1 5 10 15 <210> SEQ ID NO 186
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic
peptide
<400> SEQUENCE: 186 Asn Ser Cys Ile Leu Ser Asn Pro Gly Leu
Gly Trp Gln Cys Val Phe 1 5 10 15 <210> SEQ ID NO 187
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 187 Asn Thr Cys Lys Leu Phe Arg Ser Gly Asn
Ile Trp Gln Cys Ile Phe 1 5 10 15 <210> SEQ ID NO 188
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 188 Pro Ser Cys Arg Leu Trp Asn Pro Gly Phe
Gly Trp Glu Cys Ile Phe 1 5 10 15 <210> SEQ ID NO 189
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 189 Gln Ser Cys Thr Leu Gln Arg Leu Gly His
Leu Tyr Gln Cys Trp Phe 1 5 10 15 <210> SEQ ID NO 190
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 190 Ser Ala Cys Thr Pro Asn Trp Thr Gly Arg
Trp Trp Glu Cys Val Phe 1 5 10 15 <210> SEQ ID NO 191
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 191 Ser Lys Cys His Leu Ile Val Ser Gly Lys
Phe His Glu Cys Val Phe 1 5 10 15 <210> SEQ ID NO 192
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 192 Ser Ser Cys Thr Leu Phe Asn Pro Gly Thr
Gly Trp Thr Cys Val Phe 1 5 10 15 <210> SEQ ID NO 193
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 193 Ser Thr Cys Arg Met Gly Asn Pro Gly Gly
Val Trp Gly Cys Tyr Phe 1 5 10 15 <210> SEQ ID NO 194
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 194 Thr His Cys Leu Val Gln Trp Pro Gly Pro
Val Val Ala Cys Arg Ser 1 5 10 15 <210> SEQ ID NO 195
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 195 Thr Arg Cys Arg Leu Leu Lys Leu Gly Ser
Leu Trp Glu Cys Phe Gly 1 5 10 15 <210> SEQ ID NO 196
<211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (1)..(1) <223> OTHER INFORMATION: Any amino acid
comprising a basic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Any
amino acid comprising a basic side chain or a polar/neutral side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (4)..(4) <223> OTHER INFORMATION: Any
amino acid comprising a basic side chain or a polar/neutral side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (5)..(5) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Any
amino acid comprising an aromatic side chain or a large hydrophobic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (11)..(11) <223> OTHER INFORMATION: Any
amino acid comprising an acidic side chain <400> SEQUENCE:
196 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 <210>
SEQ ID NO 197 <211> LENGTH: 15 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (1)..(1) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Any amino acid comprising a basic side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (4)..(4) <223> OTHER INFORMATION: Any amino acid
comprising a large hydrophobic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (5)..(5)
<223> OTHER INFORMATION: Any amino acid comprising a basic
side chain or a polar/neutral side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (6)..(6)
<223> OTHER INFORMATION: Any amino acid comprising a basic
side chain or a polar/neutral side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES
<222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (11)..(11) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Any
amino acid comprising an aromatic side chain or a large hydrophobic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Any
amino acid comprising an acidic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (15)..(15)
<223> OTHER INFORMATION: Any amino acid comprising a large
hydrophobic side chain <400> SEQUENCE: 197 Xaa Cys Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Cys Xaa 1 5 10 15 <210>
SEQ ID NO 198 <211> LENGTH: 15 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 198 Ala Cys Trp Arg Ser Trp
Arg Tyr Pro Thr Arg Thr Phe Cys Ser 1 5 10 15 <210> SEQ ID NO
199 <211> LENGTH: 15 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 199 Lys Cys Arg Leu Arg Gln Met Ser
Arg Gly Gly Trp Glu Cys Leu 1 5 10 15 <210> SEQ ID NO 200
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 200 Asn Cys Arg Val Arg His Leu Pro Tyr Pro
Phe Trp Ser Cys Leu 1 5 10 15 <210> SEQ ID NO 201 <211>
LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 201 Arg Cys Arg Leu Gln Lys Ala Gly Gly Asn Thr Trp Glu
Cys Ile 1 5 10 15 <210> SEQ ID NO 202 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 202
Arg Cys Thr Leu Arg Phe Asp Ala Gln Thr Gly Trp Glu Cys Asn 1 5 10
15 <210> SEQ ID NO 203 <211> LENGTH: 15 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 203 Thr Cys Arg
Leu Lys Arg Ser Gly Pro Asn Ser Trp Glu Cys Ile 1 5 10 15
<210> SEQ ID NO 204 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 204 Thr Cys Thr Val His Arg
Ile Gly Leu Ala Glu Trp Glu Cys Val 1 5 10 15 <210> SEQ ID NO
205 <211> LENGTH: 10 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (1)..(1) <223> OTHER INFORMATION: Any
amino acid comprising a basic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Any amino acid comprising a basic
side chain or an aromatic side chain or a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (4)..(4) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Any
amino acid <400> SEQUENCE: 205 Xaa Xaa Xaa Xaa Pro Gly Xaa
Xaa Xaa Xaa 1 5 10 <210> SEQ ID NO 206 <211> LENGTH: 14
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (1)..(1)
<223> OTHER INFORMATION: Any amino acid comprising a basic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Any
amino acid comprising a basic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (4)..(4)
<223> OTHER INFORMATION: Any amino acid comprising a basic
side chain or an aromatic side chain or a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (5)..(5) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (11)..(11) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (14)..(14) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <400>
SEQUENCE: 206 Xaa Cys Xaa Xaa Xaa Xaa Pro Gly Xaa Xaa Xaa Xaa Cys
Xaa 1 5 10
<210> SEQ ID NO 207 <211> LENGTH: 16 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (1)..(1) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Any
amino acid comprising a basic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (4)..(4)
<223> OTHER INFORMATION: Any amino acid comprising a basic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (5)..(5) <223> OTHER INFORMATION: Any
amino acid comprising a basic side chain or an aromatic side chain
or a large hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (6)..(6) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (7)..(7) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (11)..(11) <223>
OTHER INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (12)..(12) <223>
OTHER INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (13)..(13) <223>
OTHER INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (15)..(15) <223>
OTHER INFORMATION: Any amino acid comprising a large hydrophobic
side chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (16)..(16) <223> OTHER INFORMATION: Any
amino acid comprising a small hydrophobic side chain <400>
SEQUENCE: 207 Xaa Xaa Cys Xaa Xaa Xaa Xaa Pro Gly Xaa Xaa Xaa Xaa
Cys Xaa Xaa 1 5 10 15 <210> SEQ ID NO 208 <211> LENGTH:
16 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 208
Val Lys Cys Lys Leu Val Asn Pro Gly Ser Gly Trp Ala Cys His Phe 1 5
10 15 <210> SEQ ID NO 209 <211> LENGTH: 16 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 209 Val Arg Cys
Phe Met Ser Glu Pro Gly Arg Val Ser Tyr Cys Thr Ala 1 5 10 15
<210> SEQ ID NO 210 <211> LENGTH: 16 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 210 Val Arg Cys Arg Leu Ala
Arg Pro Gly Leu Thr Trp Glu Cys Leu Ser 1 5 10 15 <210> SEQ
ID NO 211 <211> LENGTH: 16 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 211 Val Arg Cys Arg Val Leu Tyr Pro
Gly Gln Met Ala Val Cys Val Ser 1 5 10 15 <210> SEQ ID NO 212
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 212 Val Thr Cys Tyr Arg Ala Val Pro Gly Val
Glu Ala Tyr Cys Phe Ser 1 5 10 15 <210> SEQ ID NO 213
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 213 Val Tyr Cys Arg Arg Glu Lys Pro Gly Gly
Glu Met His Cys Arg Ser 1 5 10 15 <210> SEQ ID NO 214
<211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (1)..(1) <223> OTHER INFORMATION: Any amino acid
comprising an aromatic side chain or a large hydrophobic side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Any amino acid
comprising a large hydrophobic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (3)..(3)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (4)..(4)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (8)..(8)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (9)..(9)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (10)..(10)
<223> OTHER INFORMATION: Any amino acid comprising an
aromatic side chain or a large hydrophobic side chain <400>
SEQUENCE: 214 Xaa Xaa Xaa Xaa Pro Gly Xaa Xaa Xaa Xaa 1 5 10
<210> SEQ ID NO 215 <211> LENGTH: 14 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (1)..(1) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Any amino acid comprising an aromatic side chain or a
large hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (4)..(4) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (5)..(5) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Any
amino acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Any amino acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (11)..(11) <223> OTHER INFORMATION: Any amino acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (12)..(12) <223> OTHER INFORMATION: Any amino acid
comprising an aromatic side chain or a large hydrophobic side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (14)..(14) <223> OTHER INFORMATION: Any amino acid
<400> SEQUENCE: 215 Xaa Cys Xaa Xaa Xaa Xaa Pro Gly Xaa Xaa
Xaa Xaa Cys Xaa 1 5 10 <210> SEQ ID NO 216 <211>
LENGTH: 16 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(1)..(1) <223> OTHER INFORMATION: Any amino acid <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: Any amino acid <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(4)..(4) <223> OTHER INFORMATION: Any amino acid comprising
an aromatic side chain or a large hydrophobic side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (5)..(5) <223> OTHER INFORMATION: Any amino acid
comprising a large hydrophobic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (6)..(6)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (10)..(10)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (11)..(11)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (12)..(12)
<223> OTHER INFORMATION: Any amino acid <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (13)..(13)
<223> OTHER INFORMATION: Any amino acid comprising an
aromatic side chain or a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(15)..(15) <223> OTHER INFORMATION: Any amino acid
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (16)..(16) <223> OTHER INFORMATION: Any amino acid
comprising a large hydrophobic side chain <400> SEQUENCE: 216
Xaa Xaa Cys Xaa Xaa Xaa Xaa Pro Gly Xaa Xaa Xaa Xaa Cys Xaa Xaa 1 5
10 15 <210> SEQ ID NO 217 <211> LENGTH: 16 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 217 Ala Thr Cys
His Leu Leu Ala Pro Gly Val Asp Asn Thr Cys Ile Phe 1 5 10 15
<210> SEQ ID NO 218 <211> LENGTH: 16 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 218 His Gly Cys Thr Leu Thr
Lys Pro Gly Ala Glu Trp Val Cys Ser Phe 1 5 10 15 <210> SEQ
ID NO 219 <211> LENGTH: 16 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 219 Gln Leu Cys Pro Trp Ser Asp Pro
Gly Ser Trp Gly Pro Cys Pro Leu 1 5 10 15 <210> SEQ ID NO 220
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 220 Arg Asp Cys Ala Gly Met Glu Pro Gly Thr
Ser Val Phe Cys Asp Asn 1 5 10 15 <210> SEQ ID NO 221
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 221 Arg Asp Cys Phe Ile Leu Glu Pro Gly Thr
Ser Val Tyr Cys Asp Leu 1 5 10 15 <210> SEQ ID NO 222
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 222 Thr Asp Cys Gln Glu Thr Trp Pro Gly Asp
Arg Pro Trp Cys His Ile 1 5 10 15 <210> SEQ ID NO 223
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 223 Val Lys Cys Phe Met Ser Thr Pro Gly Gln
Ile Ala Tyr Cys Thr Thr 1 5 10 15 <210> SEQ ID NO 224
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 224 Val Lys Cys Tyr Arg Asn Ser Pro Gly Val
Glu Ala Tyr Cys Val Gly 1 5 10 15 <210> SEQ ID NO 225
<211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (1)..(1) <223> OTHER INFORMATION: Any amino acid
comprising an acidic side chain or a polar/neutral side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Any amino acid
comprising an acidic side chain or a polar/neutral side chain
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Any amino acid
comprising a large hydrophobic side chain <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (4)..(4)
<223> OTHER INFORMATION: Any amino acid comprising a
polar/neutral side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (5)..(5) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES
<222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Any
amino acid <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (7)..(7) <223> OTHER INFORMATION: Any
amino acid comprising a large hydrophobic side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(8)..(8) <223> OTHER INFORMATION: Any amino acid <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(9)..(9) <223> OTHER INFORMATION: Any amino acid <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(10)..(10) <223> OTHER INFORMATION: Any amino acid
<400> SEQUENCE: 225 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1
5 10 <210> SEQ ID NO 226 <211> LENGTH: 14 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (1)..(1) <223> OTHER
INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Any amino acid comprising an acidic side chain or a
polar/neutral side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (4)..(4) <223> OTHER
INFORMATION: Any amino acid comprising an acidic side chain or a
polar/neutral side chain <220> FEATURE: <221> NAME/KEY:
MOD_RES <222> LOCATION: (5)..(5) <223> OTHER
INFORMATION: Any amino acid comprising a large hydrophobic side
chain <220> FEATURE: <221> NAME/KEY: MOD_RES
<222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Any
amino acid comprising a polar/neutral side chain <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(7)..(7) <223> OTHER INFORMATION: Any amino acid <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(8)..(8) <223> OTHER INFORMATION: Any amino acid <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(9)..(9) <223> OTHER INFORMATION: Any amino acid comprising a
large hydrophobic side chain <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (11)..(11) <223>
OTHER INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (12)..(12) <223>
OTHER INFORMATION: Any amino acid <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (14)..(14) <223>
OTHER INFORMATION: Any amino acid <400> SEQUENCE: 226 Xaa Cys
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Cys Xaa 1 5 10 <210>
SEQ ID NO 227 <211> LENGTH: 14 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 227 Asp Cys Leu Asp Leu Arg
Gly Thr Val Gly Met Val Cys Gln 1 5 10 <210> SEQ ID NO 228
<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 228 Pro Cys Gln Arg Leu Ala Glu Tyr Tyr Ser
Gln Gln Cys Leu 1 5 10 <210> SEQ ID NO 229 <211>
LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 229 Ser Cys Met Asp Leu Lys Gly Ser Val Gly Trp Val Cys
Asp 1 5 10 <210> SEQ ID NO 230 <211> LENGTH: 14
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 230
Thr Cys Glu Ser Leu Ala Lys Met Tyr Glu Val Glu Cys Asn 1 5 10
<210> SEQ ID NO 231 <211> LENGTH: 14 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 231 Thr Cys Glu Ser Leu Ala
Arg Met Tyr Asn Glu Asn Cys Ile 1 5 10 <210> SEQ ID NO 232
<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 232 Trp Cys Trp Glu Pro His Asp Gln Tyr Tyr
Val Arg Cys Pro 1 5 10 <210> SEQ ID NO 233 <211>
LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 233 Tyr Cys His Asp Phe Lys Gly Thr Val Gly Thr Leu Cys
Ile 1 5 10 <210> SEQ ID NO 234 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 234
Gly Cys Gln Leu Val Trp Gln Asp Asp Ser Tyr Met Cys Phe Tyr 1 5 10
15 <210> SEQ ID NO 235 <211> LENGTH: 10 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <220> FEATURE: <221>
NAME/KEY: MOD_RES <222> LOCATION: (1)..(1) <223> OTHER
INFORMATION: F, I, L, M, V, W, or Y <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (6)..(6)
<223> OTHER INFORMATION: F, I, L, M, V, W, or Y <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(8)..(8) <223> OTHER INFORMATION: H, N, Q, F, I, L, M, V, W,
or Y <400> SEQUENCE: 235 Xaa Gly Gln Pro Leu Xaa Arg Xaa Gly
Ser 1 5 10 <210> SEQ ID NO 236 <211> LENGTH: 14
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <220> FEATURE:
<221> NAME/KEY: MOD_RES <222> LOCATION: (3)..(3)
<223> OTHER INFORMATION: F, I, L, M, V, W, or Y <220>
FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:
(8)..(8) <223> OTHER INFORMATION: F, I, L, M, V, W, or Y
<220> FEATURE: <221> NAME/KEY: MOD_RES <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: H, N, Q, F, I,
L, M, V, W, or Y <400> SEQUENCE: 236 Trp Cys Xaa Gly Gln Pro
Leu Xaa Arg Xaa Gly Ser Cys Lys 1 5 10 <210> SEQ ID NO 237
<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 237 Trp Cys Ile Gly Gln Pro Leu Phe Arg Gln
Gly Ser Cys Lys 1 5 10 <210> SEQ ID NO 238 <211>
LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 238 Trp Cys Val Gly Gln Pro Leu Tyr Arg Leu Gly Ser Cys
Lys 1 5 10 <210> SEQ ID NO 239 <211> LENGTH: 14
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 239
Trp Asp Gln Phe Gln Leu Gly Trp Glu Ala Gly Val Ala Ala 1 5 10
<210> SEQ ID NO 240 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 240 Phe Leu Pro Trp Pro Val
Tyr Phe Ser Gln Val Leu Gly Gly Gly 1 5 10 15 <210> SEQ ID NO
241 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 241 Tyr Val Met Cys Ser Ala Phe Gly
Cys Lys Ser Ile 1 5 10 <210> SEQ ID NO 242 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 242 His Val Ile Cys Ser Val Asn Gly Gly Cys Arg Gly 1 5
10 <210> SEQ ID NO 243 <211> LENGTH: 15 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 243 Ile Arg Phe
Cys Leu Arg Ser Glu Pro Thr Ala Cys Trp Ile Val 1 5 10 15
<210> SEQ ID NO 244 <211> LENGTH: 14 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 244 Ile Arg Cys Arg Tyr Glu
Lys Gln Ser Gly Ile Cys Leu Phe 1 5 10 <210> SEQ ID NO 245
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 245 Gly Gly Cys Ser Leu Val Trp Ala Asp Ser
Trp Val Cys Ile Phe 1 5 10 15 <210> SEQ ID NO 246 <211>
LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 246 Gly Cys Ser Leu Met Trp Gln Asp Gly Trp Trp Val Cys
Ile 1 5 10 <210> SEQ ID NO 247 <211> LENGTH: 16
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 247
Glu Trp Glu Cys Arg Phe Leu Pro Gly Arg Arg Gly Cys Ser Leu Phe 1 5
10 15 <210> SEQ ID NO 248 <211> LENGTH: 16 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 248 Lys Gly Cys
Thr Leu Gln Asn Pro Gly Ser Gly Trp Val Cys Leu Phe 1 5 10 15
<210> SEQ ID NO 249 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 249 Thr Cys Arg Leu Lys Arg
Ser Gly Pro Asn Ser Trp Glu Cys Ile 1 5 10 15 <210> SEQ ID NO
250 <211> LENGTH: 14 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 250 Trp Cys Ile Gly Gln Pro Leu Phe
Arg Gln Gly Ser Cys Lys 1 5 10 <210> SEQ ID NO 251
<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 251 Ala Val Ser Cys Asn Ser Trp Arg Cys Ile
Pro Trp 1 5 10 <210> SEQ ID NO 252 <211> LENGTH: 12
<212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 252 Ala Val Cys Cys Asp Gly
Asn Ser Cys Arg Arg Cys 1 5 10 <210> SEQ ID NO 253
<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 253 Phe Val His Cys Ser Leu Met Gly Cys Trp
Cys Gly 1 5 10 <210> SEQ ID NO 254 <211> LENGTH: 14
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 254
Arg Cys Leu Asp Leu Gly Gly Ser Val Gly Leu Val Cys Phe 1 5 10
<210> SEQ ID NO 255 <211> LENGTH: 14 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 255 Val Cys Phe Asn Phe Arg
Gly Thr Val Gly Arg His Cys Trp 1 5 10 <210> SEQ ID NO 256
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 256 Val Arg Cys Arg Gln Asn Glu Pro Gly Gly
Ala Tyr Trp Cys Ser Ser 1 5 10 15 <210> SEQ ID NO 257
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 257 Cys Val Leu Arg Glu Gly Ala Glu Gly Trp
Glu Cys Val Trp Arg 1 5 10 15 <210> SEQ ID NO 258 <211>
LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 258 Cys Arg Met Met Gln Gly Thr Tyr Gly Trp Thr Cys Leu
Phe 1 5 10 <210> SEQ ID NO 259 <211> LENGTH: 14
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 259
Cys Ile Leu Asn Asp Thr Ile Gln Gly Trp Val Cys Ile Tyr 1 5 10
<210> SEQ ID NO 260 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 260 Cys Thr Leu Tyr Arg Ser
Ala Pro Gly Val Trp Leu Cys Ile Phe 1 5 10 15 <210> SEQ ID NO
261 <211> LENGTH: 14 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 261 Cys Leu Val Phe Asp Gln Tyr Gly
Asn Tyr Lys Arg Arg Cys 1 5 10 <210> SEQ ID NO 262
<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 262 Ile Val Cys Cys Asn Met Phe Gly Cys His
Thr Cys Arg Asn 1 5 10 <210> SEQ ID NO 263 <211>
LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 263 Gln Val Cys Cys Thr Ser Arg Gly Cys Arg Val Cys Ala
Pro Val 1 5 10 15 <210> SEQ ID NO 264 <211> LENGTH: 14
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 264
Arg Val Cys Cys Ser Met Val Gly Cys Arg Ser Cys Asn Leu 1 5 10
<210> SEQ ID NO 265 <211> LENGTH: 14 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 265 Arg Val Cys Cys Thr Phe
Ala Gly Cys Arg Val Cys His Lys 1 5 10 <210> SEQ ID NO 266
<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 266 Arg Val Cys Cys Thr Ser Asp Gly Cys Arg
Gly Cys Arg Gln 1 5 10 <210> SEQ ID NO 267 <211>
LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 267 Thr Val Cys Cys Thr Val Gln Gly Cys Trp Pro Cys Ser
Arg 1 5 10 <210> SEQ ID NO 268 <211> LENGTH: 14
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 268
Val Cys Cys His Gln Thr Phe Gly Cys Tyr Arg Cys Lys Gln 1 5 10
<210> SEQ ID NO 269 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 269 Cys Val Val Cys Ser Ala
Leu Gly Cys Arg Ala Cys Val Pro Arg 1 5 10 15 <210> SEQ ID NO
270 <211> LENGTH: 18 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 270 Val Trp Asp Cys Phe Val Arg Gly
Trp Glu Ala Gly Val Ala Ala Val 1 5 10 15 Gly Glu <210> SEQ
ID NO 271 <211> LENGTH: 16 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 271 Leu Thr Cys Leu Ile Phe Lys Pro
Gly Thr His Arg His Cys Pro Val 1 5 10 15 <210> SEQ ID NO 272
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 272 Arg Tyr Cys Ser Pro Leu Ile Pro Gly Ser
Ala Leu Gly Cys Pro Arg 1 5 10 15 <210> SEQ ID NO 273
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 273 Ile Arg Cys Arg Leu Asp Pro Pro Gly Ser
Tyr Lys Thr Cys Val Phe 1 5 10 15 <210> SEQ ID NO 274
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 274 Arg Gly Val Ile Cys Asn His Ala Gly Cys
Arg Ile Trp Tyr Gly 1 5 10 15 <210> SEQ ID NO 275 <211>
LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 275 Thr Thr Gln Ser Cys Thr Leu Arg Tyr Cys Trp Leu Leu
Gln 1 5 10 <210> SEQ ID NO 276 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 276
Trp Trp Ile Ser Cys Leu Arg Asp Leu Arg Cys Leu Glu Tyr Phe 1 5 10
15 <210> SEQ ID NO 277 <211> LENGTH: 14 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 277 Arg His Ala
Cys Lys Thr Trp Tyr Arg Met Cys Ile Val Ser 1 5 10 <210> SEQ
ID NO 278 <211> LENGTH: 14 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 278 Ala Val Ser Cys Ser Arg Leu Thr
Gly Arg Cys His Ser Leu 1 5 10 <210> SEQ ID NO 279
<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 279 Trp Val Ala Cys Asn Arg Val Thr Gly Ser
Cys Arg Pro Ile 1 5 10 <210> SEQ ID NO 280 <211>
LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 280 Ser His Gly Val Cys Cys Thr Gln Ser Ser Cys Arg Ser
Cys Arg 1 5 10 15 <210> SEQ ID NO 281 <211> LENGTH: 14
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 281
Trp Val Ala Cys Asn Arg Leu Ser Gly Cys Cys Arg Pro Ile 1 5 10
<210> SEQ ID NO 282 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 282 His Thr Val Cys Cys Gln
Asp Trp Gly Cys Arg Ser Cys Ser Gly 1 5 10 15 <210> SEQ ID NO
283 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 283 Met Ala Cys Cys Thr Pro Arg Gly
Cys Arg Pro Cys 1 5 10 <210> SEQ ID NO 284 <211>
LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 284 Arg Ser Val Cys Cys Ser Ser Tyr Gly Cys Arg Ala Cys
Phe Gly 1 5 10 15 <210> SEQ ID NO 285 <211> LENGTH: 14
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 285 Cys Lys Leu Thr Cys Thr Ser Ser Thr Cys
Ser Cys Val Phe 1 5 10 <210> SEQ ID NO 286 <211>
LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 286 Cys Met Leu Lys Cys Thr Asn Ala Ile Cys Glu Cys Ile
Phe 1 5 10 <210> SEQ ID NO 287 <211> LENGTH: 14
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 287
Cys Arg Val Trp Cys Asn Gln Ala Glu Cys Met Cys Ile Phe 1 5 10
<210> SEQ ID NO 288 <211> LENGTH: 14 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 288 Ser Arg Cys Ser Phe Asp
Val Thr Lys Gln Glu Cys Val Phe 1 5 10 <210> SEQ ID NO 289
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 289 Leu Glu Cys Gln Pro Tyr Arg Gly Pro Leu
Tyr Tyr Cys Gln Asp 1 5 10 15 <210> SEQ ID NO 290 <211>
LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 290 Ser Ile Cys Cys Thr Pro Gln Leu Cys His Ser Cys Asp
Gly 1 5 10 <210> SEQ ID NO 291 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 291
Thr Thr Cys Cys Thr Ser Glu Gly Cys His Lys Cys Ile Thr Leu 1 5 10
15 <210> SEQ ID NO 292 <211> LENGTH: 14 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 292 Cys Val Ala
Cys Ser Ser Asp Gly Cys Ser Pro Ile Ile Cys 1 5 10 <210> SEQ
ID NO 293 <211> LENGTH: 15 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 293 Ala Ile Cys Ser Glu Asp Glu Gly
Gly Glu Leu Cys Cys Trp His 1 5 10 15 <210> SEQ ID NO 294
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 294 His Glu Ile Cys Cys Gly Pro Pro Gly Cys
His Ser Cys Ser Val Thr 1 5 10 15 <210> SEQ ID NO 295
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 295 Leu Ser Val Cys Ser Cys Pro Pro Gly Gln
Leu Tyr Cys Met Val Glu 1 5 10 15 <210> SEQ ID NO 296
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 296 Ser Thr Trp Cys Cys Leu His Pro Gly Val
Gly Glu Cys Gln Ala Val 1 5 10 15 <210> SEQ ID NO 297
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 297 Val Thr Gln Cys Phe Asp Gly Pro Gly Ser
Phe Arg Cys Cys Tyr Gln 1 5 10 15 <210> SEQ ID NO 298
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 298 Arg Gln Cys Asn Cys Leu Ser Pro Gly Glu
Leu Val Asn Cys Gln Gln 1 5 10 15 <210> SEQ ID NO 299
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 299 Met Val Ser Cys Thr Asp Leu Gly Cys Val
Val Val Gly Gly Gly 1 5 10 15 <210> SEQ ID NO 300 <211>
LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 300 Val Val His Cys Leu Gln Ser Gly Cys Tyr Ser Val Gly
Ser Gly 1 5 10 15 <210> SEQ ID NO 301 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 301
Thr Ile Lys Cys Gly Ser Ser Gly Trp Cys Trp Val Glu Ala Gly 1 5 10
15 <210> SEQ ID NO 302 <211> LENGTH: 15 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 302
Met Val Ser Cys Thr Asp Leu Gly Cys Val Val Val Gly Gly Gly 1 5 10
15 <210> SEQ ID NO 303 <211> LENGTH: 16 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 303 His Glu Ile
Cys Cys Gly Pro Pro Gly Cys His Ser Cys Ser Val Thr 1 5 10 15
<210> SEQ ID NO 304 <211> LENGTH: 16 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 304 Leu Ser Val Cys Ser Cys
Pro Pro Gly Gln Leu Tyr Cys Met Val Glu 1 5 10 15 <210> SEQ
ID NO 305 <211> LENGTH: 16 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 305 Ser Thr Trp Cys Cys Leu His Pro
Gly Val Gly Glu Cys Gln Ala Val 1 5 10 15 <210> SEQ ID NO 306
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 306 Val Thr Gln Cys Phe Asp Gly Pro Gly Ser
Phe Arg Cys Cys Tyr Gln 1 5 10 15 <210> SEQ ID NO 307
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 307 Arg Gln Cys Asn Cys Leu Ser Pro Gly Glu
Leu Val Asn Cys Gln Gln 1 5 10 15 <210> SEQ ID NO 308
<211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 308 Phe Val Arg Cys Ser Ala Asn Gly Cys Val 1
5 10 <210> SEQ ID NO 309 <211> LENGTH: 10 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 309 Ser Val Arg
Cys Ser Ala Ser Gly Cys Val 1 5 10 <210> SEQ ID NO 310
<211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 310 Tyr Val Ala Cys Ser Val Ser Gly Cys Val 1
5 10 <210> SEQ ID NO 311 <211> LENGTH: 10 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 311 Tyr Val Ile
Cys Gly Ala Ser Gly Cys Val 1 5 10 <210> SEQ ID NO 312
<211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 312 Tyr Val Arg Cys Thr Ala Ile Gly Cys Val 1
5 10 <210> SEQ ID NO 313 <211> LENGTH: 10 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 313 Phe Val Arg
Cys Ser Ala Thr Gly Cys Val 1 5 10 <210> SEQ ID NO 314
<211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 314 Tyr Val Ile Cys Ser Ala Ser Gly Cys Val 1
5 10 <210> SEQ ID NO 315 <211> LENGTH: 10 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 315 Trp Val Arg
Cys Ser Ala Ser Gly Cys Val 1 5 10 <210> SEQ ID NO 316
<211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 316 Phe Val Arg Cys Ser Ala Ser Gly Cys Val 1
5 10 <210> SEQ ID NO 317 <211> LENGTH: 10 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 317 Phe Val Arg
Cys Thr Ala Ser Gly Cys Val 1 5 10 <210> SEQ ID NO 318
<211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 318 Phe Val Arg Cys Thr Ser Asp Gly Cys Val 1
5 10
<210> SEQ ID NO 319 <211> LENGTH: 10 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 319 Tyr Val Arg Cys Thr Ala
Ser Gly Cys Val 1 5 10 <210> SEQ ID NO 320 <211>
LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 320 Phe Arg Arg Cys Ser Ala Ser Gly Cys Val 1 5 10
<210> SEQ ID NO 321 <211> LENGTH: 10 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 321 Leu Arg Arg Cys Ser Ala
Asn Gly Cys Val 1 5 10 <210> SEQ ID NO 322 <211>
LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 322 Leu Arg Arg Cys Ser Ala Asn Gly Cys Val 1 5 10
<210> SEQ ID NO 323 <211> LENGTH: 10 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 323 Phe Val Arg Cys Ser Leu
Ile Gly Cys Val 1 5 10 <210> SEQ ID NO 324 <211>
LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 324 Phe Val Arg Cys Asn Ala Ser Gly Cys Val 1 5 10
<210> SEQ ID NO 325 <211> LENGTH: 10 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 325 Phe Val Arg Cys Thr Arg
Glu Gly Cys Val 1 5 10 <210> SEQ ID NO 326 <211>
LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 326 Phe Val Arg Cys Thr Ser Asp Gly Cys Val 1 5 10
<210> SEQ ID NO 327 <211> LENGTH: 10 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 327 Tyr Val Ile Cys Ser Ala
Ser Gly Cys Val 1 5 10 <210> SEQ ID NO 328 <211>
LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 328 Phe Val Arg Cys Thr Glu Trp Gly Cys Val 1 5 10
<210> SEQ ID NO 329 <211> LENGTH: 10 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 329 Phe Val Arg Cys Thr Ala
Ser Gly Cys Ile 1 5 10 <210> SEQ ID NO 330 <211>
LENGTH: 16 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 330 Tyr Val Arg Cys Ser Glu Ser Gly Cys Val Gly Ser Ser
Trp Asn Ala 1 5 10 15 <210> SEQ ID NO 331 <211> LENGTH:
16 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 331
Phe Val Arg Cys Ser Glu Ser Gly Cys Val Gly Ser Ser Trp Ser Ala 1 5
10 15 <210> SEQ ID NO 332 <211> LENGTH: 16 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 332 Tyr Val Arg
Cys Ser Ala Ser Gly Cys Val Gly Ser Ser Trp Phe Leu 1 5 10 15
<210> SEQ ID NO 333 <211> LENGTH: 16 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 333 Tyr Val Arg Cys Ser Asp
Ser Gly Cys Val Gly Ser Thr Trp Gly Trp 1 5 10 15 <210> SEQ
ID NO 334 <211> LENGTH: 16 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 334 Tyr Val Arg Cys Ser Glu Ser Gly
Cys Val Gly Ser Thr Trp Val Phe 1 5 10 15 <210> SEQ ID NO 335
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 335
Tyr Val Arg Cys Ser Glu Ser Gly Cys Val Gly Ser Thr Trp Val Phe 1 5
10 15 <210> SEQ ID NO 336 <211> LENGTH: 16 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 336 Tyr Val Leu
Cys Ala Leu Ser Gly Cys Val Gly Ser Ser Trp Ser Ser 1 5 10 15
<210> SEQ ID NO 337 <211> LENGTH: 16 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 337 Tyr Val Arg Cys Gly Glu
Ser Gly Cys Val Gly Ser Thr Trp Ser Thr 1 5 10 15 <210> SEQ
ID NO 338 <211> LENGTH: 16 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 338 Tyr Val Arg Cys Ser Ala Thr Gly
Cys Val Gly Ser Thr Trp Thr Phe 1 5 10 15 <210> SEQ ID NO 339
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 339 Tyr Val Arg Cys Gly Glu Thr Gly Cys Val
Gly Ser Thr Trp Ser Phe 1 5 10 15 <210> SEQ ID NO 340
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 340 Tyr Val Arg Cys Gly Val Ser Gly Cys Val
Gly Ser Ser Trp Val Leu 1 5 10 15 <210> SEQ ID NO 341
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 341 Tyr Val Arg Cys Gly Glu Ser Gly Cys Val
Gly Ser Thr Trp Ser Thr 1 5 10 15 <210> SEQ ID NO 342
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 342 Phe Val Arg Cys Ser Glu Ser Gly Cys Val
Gly Ser Ser Trp Ser Thr 1 5 10 15 <210> SEQ ID NO 343
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 343 Tyr Val Arg Cys Ser Glu Ser Gly Cys Val
Gly Ser Ser Trp Trp Ala 1 5 10 15 <210> SEQ ID NO 344
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 344 Tyr Val Arg Cys Ser Val Thr Gly Cys Val
Gly Ser Ser Trp Ser Ile 1 5 10 15 <210> SEQ ID NO 345
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 345 Tyr Val Arg Cys Ser Val Thr Gly Cys Val
Gly Ser Ser Trp Ser Ile 1 5 10 15 <210> SEQ ID NO 346
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 346 Tyr Val Arg Cys Ser Glu Ser Gly Cys Val
Gly Ser Ser Trp Ser Val 1 5 10 15 <210> SEQ ID NO 347
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 347 Phe Val Arg Cys Ser Ala Asp Gly Cys Val
Gly Ser Ser Trp Leu Gln 1 5 10 15 <210> SEQ ID NO 348
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 348 Tyr Val Arg Cys Ser Ala Asp Gly Cys Val
Gly Ser Ser Trp Ile Thr 1 5 10 15 <210> SEQ ID NO 349
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 349 Tyr Val Arg Cys Asn Pro Ser Gly Cys Val
Gly Ser Ser Trp Ser Ile 1 5 10 15 <210> SEQ ID NO 350
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 350 Tyr Val Arg Cys Ser Val Thr Gly Cys Val
Gly Ser Ser Trp Ser Ile 1 5 10 15 <210> SEQ ID NO 351
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 351 Tyr Val Arg Cys Ser Glu Ser Gly Cys Val
Gly Ser Ser Trp Ser Val 1 5 10 15 <210> SEQ ID NO 352
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 352 Phe Val Arg Cys Ser Ala Asn Gly
Cys Val Gly Ser Thr Trp Gln Ala 1 5 10 15 <210> SEQ ID NO 353
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 353 Tyr Val Arg Cys Thr Glu Ser Gly Cys Val
Gly Ser Thr Trp Thr Tyr 1 5 10 15 <210> SEQ ID NO 354
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 354 Tyr Val Arg Cys Ser Val Thr Gly Cys Val
Gly Ser Thr Trp Ser Val 1 5 10 15 <210> SEQ ID NO 355
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 355 Tyr Val Arg Cys Ser Glu Ile Gly Cys Val
Gly Ser Thr Trp Ser Leu 1 5 10 15 <210> SEQ ID NO 356
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 356 Thr Val Arg Cys Ser Ala Thr Gly Cys Val
Gly Ser Ser Trp Val Gly 1 5 10 15 <210> SEQ ID NO 357
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 357 Tyr Val Arg Cys Ser Ala Thr Gly Cys Val
Gly Ser Ser Trp Val Gly 1 5 10 15 <210> SEQ ID NO 358
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 358 Phe Val Arg Cys Ser Ala Ser Gly Cys Val
Gly Ser Ser Trp Val Gly 1 5 10 15 <210> SEQ ID NO 359
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 359 Tyr Val Arg Cys Ser Ala Asp Gly Cys Val
Gly Ser Thr Trp Asn Leu 1 5 10 15 <210> SEQ ID NO 360
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 360 Tyr Val Arg Ser Ser Gln Ser Gly Cys Val
Gly Ser Gly Trp Val Leu 1 5 10 15 <210> SEQ ID NO 361
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 361 Tyr Val Ala Cys Ser Glu Ser Gly Cys Val
Gly Ser Ser Trp Ser Val 1 5 10 15 <210> SEQ ID NO 362
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 362 Phe Val Ala Cys Gly Glu Leu Gly Cys Val
Gly Ser Ser Trp Ser Ile 1 5 10 15 <210> SEQ ID NO 363
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 363 Tyr Val Ala Cys Ser Glu Ser Gly Cys Val
Gly Ser Ser Trp Leu Ala 1 5 10 15 <210> SEQ ID NO 364
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 364 Tyr Cys Arg Cys Thr Glu Ser Gly Cys Val
Gly Ser Thr Trp Thr Tyr 1 5 10 15 <210> SEQ ID NO 365
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 365 Phe Val Arg Cys Thr Ala Ile Gly Cys Val
Gly Ser Ser Trp Ser Val 1 5 10 15 <210> SEQ ID NO 366
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 366 Tyr Val Arg Cys Ser Ala Asp Gly Cys Val
Gly Ser Ser Trp Ser Ala 1 5 10 15 <210> SEQ ID NO 367
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 367 Tyr Val Arg Cys Ser Ala Ser Gly Cys Val
Gly Ser Ser Trp Asn Tyr 1 5 10 15 <210> SEQ ID NO 368
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 368 Tyr Val Leu Cys Ser Ala Ser Gly Cys Val
Gly Ser Leu Trp Thr His 1 5 10 15 <210> SEQ ID NO 369
<211> LENGTH: 16 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 369 Tyr Val Arg Cys Thr Asp
Ser Gly Cys Val Gly Ser Ser Trp His Leu 1 5 10 15 <210> SEQ
ID NO 370 <211> LENGTH: 16 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 370 Tyr Val Ala Cys Ser Glu Ser Gly
Cys Val Gly Ser Thr Trp Ile Thr 1 5 10 15 <210> SEQ ID NO 371
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 371 Tyr Val Ala Cys Ser Glu Ser Gly Cys Val
Gly Ser Thr Trp Thr Phe 1 5 10 15 <210> SEQ ID NO 372
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 372 Tyr Val Arg Cys Gly Ala Ala Gly Cys Val
Val Ser Ser Trp Val Tyr 1 5 10 15 <210> SEQ ID NO 373
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 373 Phe Val Arg Cys Gly Ala Ser Gly Cys Val
Gly Ser Thr Trp Gly Ser 1 5 10 15 <210> SEQ ID NO 374
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 374 Tyr Val Ala Cys Ser Glu Ile Gly Cys Val
Gly Ser Thr Trp Ser Leu 1 5 10 15 <210> SEQ ID NO 375
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 375 Tyr Val Ala Cys Ser Glu Ser Gly Cys Val
Gly Ser Ser Trp Thr Trp 1 5 10 15 <210> SEQ ID NO 376
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 376 Tyr Val Ala Cys Ser Val Ser Gly Cys Val
Gly Ser Ser Trp Ser Val 1 5 10 15 <210> SEQ ID NO 377
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 377 Tyr Val Arg Cys Ser Glu Ser Gly Cys Val
Gly Ser Thr Trp Thr Thr 1 5 10 15 <210> SEQ ID NO 378
<211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 378 Tyr Val Arg Cys Ser Glu Ser Gly Cys Val
Ser Ser Phe Trp Ser Ala 1 5 10 15 Pro Trp Lys Ala 20 <210>
SEQ ID NO 379 <211> LENGTH: 20 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 379 Tyr Val Arg Cys Ser Glu
Asn Gly Cys Val Gly His Ser Trp Thr Gln 1 5 10 15 Gly Leu Arg Thr
20 <210> SEQ ID NO 380 <211> LENGTH: 20 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 380 Tyr Val Arg
Cys Ser Glu Ser Gly Cys Val Ser Gln Arg Pro His Val 1 5 10 15 Leu
Glu Val Trp 20 <210> SEQ ID NO 381 <211> LENGTH: 20
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 381
Tyr Val Leu Cys Ser Glu Arg Gly Cys Val Gly Gln Asn Trp Ala Val 1 5
10 15 Gly Lys Leu Pro 20 <210> SEQ ID NO 382 <211>
LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 382 Tyr Val Arg Cys Ser Glu Ile Gly Cys Val Gly Ser His
Trp Ser Ser 1 5 10 15 Tyr Gly Lys His 20 <210> SEQ ID NO 383
<211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 383 Tyr Val Arg Cys Ser Glu Asn Gly Cys Val
Gly Ser Ser Trp Gly Arg 1 5 10 15 Val Thr Leu Asp 20 <210>
SEQ ID NO 384 <211> LENGTH: 20 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 384
Tyr Val Arg Cys Ser Glu Ser Gly Cys Val Gly Cys Glu Leu Val Trp 1 5
10 15 Tyr Phe Ile Thr 20 <210> SEQ ID NO 385 <211>
LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 385 Tyr Val Arg Cys Ser Glu Ser Gly Cys Val Gly Ser Ser
Trp Gly Ala 1 5 10 15 Val Ala Ser Ile 20 <210> SEQ ID NO 386
<211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 386 Tyr Val Arg Cys Ser Glu Ser Gly Cys Val
Gly Ser Ser Trp Gly Ala 1 5 10 15 Val Ala Ser Ile 20 <210>
SEQ ID NO 387 <211> LENGTH: 20 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 387 Tyr Val Arg Cys Ser Glu
Ser Gly Cys Val Gly Ser Ser Trp Ser Val 1 5 10 15 Ser Pro Arg Gly
20 <210> SEQ ID NO 388 <211> LENGTH: 20 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 388 Tyr Val Arg
Cys Gly Glu Ser Gly Cys Val Ser Ser Ser Trp Ser Thr 1 5 10 15 Met
Gly Asn Ser 20 <210> SEQ ID NO 389 <211> LENGTH: 20
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 389
Tyr Val Arg Cys Ser Glu Asn Gly Cys Val Gly Ser Ser Trp Glu His 1 5
10 15 Ser Ala Ile Ile 20 <210> SEQ ID NO 390 <211>
LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 390 Tyr Val Arg Cys Ser Glu Gly Gly Cys Val Gly Ser Thr
Trp Thr Ala 1 5 10 15 Ser Tyr Pro Asn 20 <210> SEQ ID NO 391
<211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 391 Tyr Val Arg Cys Ser Glu Ser Gly Cys Val
Gly Ser Thr Trp Asn Gly 1 5 10 15 Val Leu Ser Arg 20 <210>
SEQ ID NO 392 <211> LENGTH: 20 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 392 Tyr Val Arg Cys Ser Glu
Ser Gly Cys Val Gly Ser Thr Trp Asn Gly 1 5 10 15 Val Leu Ser Arg
20 <210> SEQ ID NO 393 <211> LENGTH: 20 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 393 Thr Val Arg
Cys Ser Gln Ser Gly Cys Val Gly Cys Gln Leu Val Trp 1 5 10 15 Tyr
Phe Thr Thr 20 <210> SEQ ID NO 394 <211> LENGTH: 20
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 394
Tyr Val Asn Cys Ser Gln Ser Gly Cys Val Gly Ser Thr Trp Asn Gly 1 5
10 15 Val Phe Ser Asn 20 <210> SEQ ID NO 395 <211>
LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 395 Tyr Val Ala Cys Ser Glu Ser Gly Cys Val Ser Val Asp
Ser Ser Ala 1 5 10 15 Gly Ala Leu Phe 20 <210> SEQ ID NO 396
<211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 396 Tyr Val Arg Cys Asn Glu Thr Gly Cys Val
Gly Ser Ser Trp Ile Ala 1 5 10 15 Ala Gly Pro Phe 20 <210>
SEQ ID NO 397 <211> LENGTH: 20 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 397 Tyr Val Arg Cys Ser Glu
Ser Gly Cys Val Gly Ser Thr Trp Leu Phe 1 5 10 15 Asn Pro Trp Gly
20 <210> SEQ ID NO 398 <400> SEQUENCE: 398 000
<210> SEQ ID NO 399 <400> SEQUENCE: 399
000 <210> SEQ ID NO 400 <211> LENGTH: 18 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 400 Trp Asp Asp
Phe Ile Leu Gly Trp Glu Ala Gly Val Ala Ala Val Gly 1 5 10 15 Glu
Val <210> SEQ ID NO 401 <211> LENGTH: 16 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 401 Phe Leu Pro
Trp Pro Val Tyr Phe Ser Gln Val Leu Gly Gly Arg Arg 1 5 10 15
<210> SEQ ID NO 402 <211> LENGTH: 14 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 402 Tyr Val Met Cys Ser Ala
Phe Gly Cys Lys Ser Ile Gly Gly 1 5 10 <210> SEQ ID NO 403
<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 403 His Val Ile Cys Ser Val Asn Gly Gly Cys
Arg Gly Gly Gly 1 5 10 <210> SEQ ID NO 404 <211>
LENGTH: 19 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 404 Gly Gly Ile Arg Phe Cys Leu Arg Ser Glu Pro Thr Ala
Cys Trp Ile 1 5 10 15 Val Gly Gly <210> SEQ ID NO 405
<211> LENGTH: 18 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 405 Gly Gly Ile Arg Cys Arg Tyr Glu Lys Gln
Ser Gly Ile Cys Leu Phe 1 5 10 15 Gly Gly <210> SEQ ID NO 406
<211> LENGTH: 18 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 406 Gly Gly Gly Cys Ser Leu Met Trp Gln Asp
Gly Trp Trp Val Cys Ile 1 5 10 15 Gly Gly <210> SEQ ID NO 407
<211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 407 Gly Gly Glu Trp Glu Cys Arg Phe Leu Pro
Gly Arg Arg Gly Cys Ser 1 5 10 15 Leu Phe Gly Gly 20 <210>
SEQ ID NO 408 <211> LENGTH: 20 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 408 Gly Gly Lys Gly Cys Thr
Leu Gln Asn Pro Gly Ser Gly Trp Val Cys 1 5 10 15 Leu Phe Gly Gly
20 <210> SEQ ID NO 409 <211> LENGTH: 19 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 409 Gly Gly Thr
Cys Arg Leu Lys Arg Ser Gly Pro Asn Ser Trp Glu Cys 1 5 10 15 Ile
Gly Gly <210> SEQ ID NO 410 <211> LENGTH: 18
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 410
Gly Gly Trp Cys Ile Gly Gln Pro Leu Phe Arg Gln Gly Ser Cys Lys 1 5
10 15 Gly Gly <210> SEQ ID NO 411 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 411
Phe Val Leu Cys Gly Leu Gln Gly Cys Arg Ser Gly Gly 1 5 10
<210> SEQ ID NO 412 <211> LENGTH: 14 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 412 Phe Val Pro Trp Asp Glu
Tyr Phe Leu Gln Ile Leu Gly Gly 1 5 10 <210> SEQ ID NO 413
<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 413 Gly Gly Gly Trp Val Ile Cys Ser Ala Leu
Gly Cys Pro Phe Gly Gly 1 5 10 15 <210> SEQ ID NO 414
<211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 414 Gly Gly Gly Arg Arg Phe Cys Leu Arg Ser
Glu Pro Thr Ala Cys Trp 1 5 10 15 Thr Val Gly Gly 20 <210>
SEQ ID NO 415
<211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 415 Gly Gly Gly Ser Arg Cys Ser Leu Val Trp
Ala Asp Ser Trp Val Cys 1 5 10 15 Ile Phe Gly Gly 20 <210>
SEQ ID NO 416 <211> LENGTH: 20 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 416 Gly Gly Asp Trp Glu Cys
Leu Phe Leu Pro Gly Arg Arg Gly Cys Thr 1 5 10 15 Leu Phe Gly Gly
20 <210> SEQ ID NO 417 <211> LENGTH: 14 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 417 Phe Ile Pro
Trp Asp Glu Tyr Phe Ala Gln Leu Leu Gly Gly 1 5 10 <210> SEQ
ID NO 418 <211> LENGTH: 14 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 418 Phe Val Pro Trp Asp Val Tyr Phe
Ser Gln Ile Leu Gly Gly 1 5 10 <210> SEQ ID NO 419
<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 419 Phe Ile Pro Trp Asp Glu Tyr Phe Lys Gln
Val Leu Gly Gly 1 5 10 <210> SEQ ID NO 420 <211>
LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 420 Phe Val Pro Trp Pro Glu Tyr Phe Leu Gln Ile Met Gly
Gly 1 5 10 <210> SEQ ID NO 421 <211> LENGTH: 14
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 421
Phe Ile Pro Trp Glu Glu Tyr Phe Ser Gln Leu Leu Gly Gly 1 5 10
<210> SEQ ID NO 422 <211> LENGTH: 14 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 422 Phe Ile Pro Trp Pro Glu
Tyr Phe Ser Gln Leu Leu Gly Gly 1 5 10 <210> SEQ ID NO 423
<211> LENGTH: 19 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 423 Gly Gly Gly Gly Cys Ser Leu Val Trp Ala
Asp Ser Trp Val Cys Ile 1 5 10 15 Phe Gly Gly <210> SEQ ID NO
424 <400> SEQUENCE: 424 000 <210> SEQ ID NO 425
<400> SEQUENCE: 425 000 <210> SEQ ID NO 426 <400>
SEQUENCE: 426 000 <210> SEQ ID NO 427 <400> SEQUENCE:
427 000 <210> SEQ ID NO 428 <400> SEQUENCE: 428 000
<210> SEQ ID NO 429 <400> SEQUENCE: 429 000 <210>
SEQ ID NO 430 <400> SEQUENCE: 430 000 <210> SEQ ID NO
431 <400> SEQUENCE: 431 000 <210> SEQ ID NO 432
<400> SEQUENCE: 432 000 <210> SEQ ID NO 433 <400>
SEQUENCE: 433 000 <210> SEQ ID NO 434 <400> SEQUENCE:
434 000 <210> SEQ ID NO 435 <400> SEQUENCE: 435 000
<210> SEQ ID NO 436 <400> SEQUENCE: 436 000 <210>
SEQ ID NO 437 <400> SEQUENCE: 437 000 <210> SEQ ID NO
438 <400> SEQUENCE: 438 000 <210> SEQ ID NO 439
<400> SEQUENCE: 439
000 <210> SEQ ID NO 440 <400> SEQUENCE: 440 000
<210> SEQ ID NO 441 <400> SEQUENCE: 441 000 <210>
SEQ ID NO 442 <400> SEQUENCE: 442 000 <210> SEQ ID NO
443 <400> SEQUENCE: 443 000 <210> SEQ ID NO 444
<400> SEQUENCE: 444 000 <210> SEQ ID NO 445 <400>
SEQUENCE: 445 000 <210> SEQ ID NO 446 <400> SEQUENCE:
446 000 <210> SEQ ID NO 447 <400> SEQUENCE: 447 000
<210> SEQ ID NO 448 <400> SEQUENCE: 448 000 <210>
SEQ ID NO 449 <400> SEQUENCE: 449 000 <210> SEQ ID NO
450 <400> SEQUENCE: 450 000 <210> SEQ ID NO 451
<400> SEQUENCE: 451 000 <210> SEQ ID NO 452 <400>
SEQUENCE: 452 000 <210> SEQ ID NO 453 <400> SEQUENCE:
453 000 <210> SEQ ID NO 454 <400> SEQUENCE: 454 000
<210> SEQ ID NO 455 <400> SEQUENCE: 455 000 <210>
SEQ ID NO 456 <400> SEQUENCE: 456 000 <210> SEQ ID NO
457 <400> SEQUENCE: 457 000 <210> SEQ ID NO 458
<400> SEQUENCE: 458 000 <210> SEQ ID NO 459 <400>
SEQUENCE: 459 000 <210> SEQ ID NO 460 <400> SEQUENCE:
460 000 <210> SEQ ID NO 461 <400> SEQUENCE: 461 000
<210> SEQ ID NO 462 <400> SEQUENCE: 462 000 <210>
SEQ ID NO 463 <400> SEQUENCE: 463 000 <210> SEQ ID NO
464 <400> SEQUENCE: 464 000 <210> SEQ ID NO 465
<400> SEQUENCE: 465 000 <210> SEQ ID NO 466 <400>
SEQUENCE: 466 000 <210> SEQ ID NO 467 <400> SEQUENCE:
467 000 <210> SEQ ID NO 468 <400> SEQUENCE: 468 000
<210> SEQ ID NO 469 <400> SEQUENCE: 469 000 <210>
SEQ ID NO 470 <400> SEQUENCE: 470 000 <210> SEQ ID NO
471 <400> SEQUENCE: 471 000 <210> SEQ ID NO 472
<400> SEQUENCE: 472 000 <210> SEQ ID NO 473 <400>
SEQUENCE: 473 000 <210> SEQ ID NO 474 <400> SEQUENCE:
474 000 <210> SEQ ID NO 475 <400> SEQUENCE: 475
000 <210> SEQ ID NO 476 <400> SEQUENCE: 476 000
<210> SEQ ID NO 477 <400> SEQUENCE: 477 000 <210>
SEQ ID NO 478 <400> SEQUENCE: 478 000 <210> SEQ ID NO
479 <400> SEQUENCE: 479 000 <210> SEQ ID NO 480
<400> SEQUENCE: 480 000 <210> SEQ ID NO 481 <400>
SEQUENCE: 481 000 <210> SEQ ID NO 482 <400> SEQUENCE:
482 000 <210> SEQ ID NO 483 <400> SEQUENCE: 483 000
<210> SEQ ID NO 484 <400> SEQUENCE: 484 000 <210>
SEQ ID NO 485 <400> SEQUENCE: 485 000 <210> SEQ ID NO
486 <400> SEQUENCE: 486 000 <210> SEQ ID NO 487
<400> SEQUENCE: 487 000 <210> SEQ ID NO 488 <400>
SEQUENCE: 488 000 <210> SEQ ID NO 489 <400> SEQUENCE:
489 000 <210> SEQ ID NO 490 <400> SEQUENCE: 490 000
<210> SEQ ID NO 491 <400> SEQUENCE: 491 000 <210>
SEQ ID NO 492 <400> SEQUENCE: 492 000 <210> SEQ ID NO
493 <400> SEQUENCE: 493 000 <210> SEQ ID NO 494
<400> SEQUENCE: 494 000 <210> SEQ ID NO 495 <400>
SEQUENCE: 495 000 <210> SEQ ID NO 496 <400> SEQUENCE:
496 000 <210> SEQ ID NO 497 <400> SEQUENCE: 497 000
<210> SEQ ID NO 498 <400> SEQUENCE: 498 000 <210>
SEQ ID NO 499 <400> SEQUENCE: 499 000 <210> SEQ ID NO
500 <400> SEQUENCE: 500 000 <210> SEQ ID NO 501
<400> SEQUENCE: 501 000 <210> SEQ ID NO 502 <400>
SEQUENCE: 502 000 <210> SEQ ID NO 503 <400> SEQUENCE:
503 000 <210> SEQ ID NO 504 <400> SEQUENCE: 504 000
<210> SEQ ID NO 505 <400> SEQUENCE: 505 000 <210>
SEQ ID NO 506 <400> SEQUENCE: 506 000 <210> SEQ ID NO
507 <400> SEQUENCE: 507 000 <210> SEQ ID NO 508
<400> SEQUENCE: 508 000 <210> SEQ ID NO 509 <400>
SEQUENCE: 509 000 <210> SEQ ID NO 510 <400> SEQUENCE:
510 000 <210> SEQ ID NO 511
<400> SEQUENCE: 511 000 <210> SEQ ID NO 512 <400>
SEQUENCE: 512 000 <210> SEQ ID NO 513 <400> SEQUENCE:
513 000 <210> SEQ ID NO 514 <400> SEQUENCE: 514 000
<210> SEQ ID NO 515 <400> SEQUENCE: 515 000 <210>
SEQ ID NO 516 <400> SEQUENCE: 516 000 <210> SEQ ID NO
517 <400> SEQUENCE: 517 000 <210> SEQ ID NO 518
<400> SEQUENCE: 518 000 <210> SEQ ID NO 519 <400>
SEQUENCE: 519 000 <210> SEQ ID NO 520 <400> SEQUENCE:
520 000 <210> SEQ ID NO 521 <400> SEQUENCE: 521 000
<210> SEQ ID NO 522 <400> SEQUENCE: 522 000 <210>
SEQ ID NO 523 <400> SEQUENCE: 523 000 <210> SEQ ID NO
524 <400> SEQUENCE: 524 000 <210> SEQ ID NO 525
<400> SEQUENCE: 525 000 <210> SEQ ID NO 526 <400>
SEQUENCE: 526 000 <210> SEQ ID NO 527 <400> SEQUENCE:
527 000 <210> SEQ ID NO 528 <400> SEQUENCE: 528 000
<210> SEQ ID NO 529 <400> SEQUENCE: 529 000 <210>
SEQ ID NO 530 <400> SEQUENCE: 530 000 <210> SEQ ID NO
531 <400> SEQUENCE: 531 000 <210> SEQ ID NO 532
<400> SEQUENCE: 532 000 <210> SEQ ID NO 533 <400>
SEQUENCE: 533 000 <210> SEQ ID NO 534 <400> SEQUENCE:
534 000 <210> SEQ ID NO 535 <400> SEQUENCE: 535 000
<210> SEQ ID NO 536 <400> SEQUENCE: 536 000 <210>
SEQ ID NO 537 <400> SEQUENCE: 537 000 <210> SEQ ID NO
538 <400> SEQUENCE: 538 000 <210> SEQ ID NO 539
<400> SEQUENCE: 539 000 <210> SEQ ID NO 540 <400>
SEQUENCE: 540 000 <210> SEQ ID NO 541 <400> SEQUENCE:
541 000 <210> SEQ ID NO 542 <400> SEQUENCE: 542 000
<210> SEQ ID NO 543 <400> SEQUENCE: 543 000 <210>
SEQ ID NO 544 <400> SEQUENCE: 544 000 <210> SEQ ID NO
545 <400> SEQUENCE: 545 000 <210> SEQ ID NO 546
<400> SEQUENCE: 546 000 <210> SEQ ID NO 547
<400> SEQUENCE: 547 000 <210> SEQ ID NO 548 <400>
SEQUENCE: 548 000 <210> SEQ ID NO 549 <400> SEQUENCE:
549 000 <210> SEQ ID NO 550 <400> SEQUENCE: 550 000
<210> SEQ ID NO 551 <400> SEQUENCE: 551 000 <210>
SEQ ID NO 552 <400> SEQUENCE: 552 000 <210> SEQ ID NO
553 <400> SEQUENCE: 553 000 <210> SEQ ID NO 554
<400> SEQUENCE: 554 000 <210> SEQ ID NO 555 <400>
SEQUENCE: 555 000 <210> SEQ ID NO 556 <400> SEQUENCE:
556 000 <210> SEQ ID NO 557 <400> SEQUENCE: 557 000
<210> SEQ ID NO 558 <400> SEQUENCE: 558 000 <210>
SEQ ID NO 559 <400> SEQUENCE: 559 000 <210> SEQ ID NO
560 <400> SEQUENCE: 560 000 <210> SEQ ID NO 561
<400> SEQUENCE: 561 000 <210> SEQ ID NO 562 <400>
SEQUENCE: 562 000 <210> SEQ ID NO 563 <400> SEQUENCE:
563 000 <210> SEQ ID NO 564 <400> SEQUENCE: 564 000
<210> SEQ ID NO 565 <400> SEQUENCE: 565 000 <210>
SEQ ID NO 566 <400> SEQUENCE: 566 000 <210> SEQ ID NO
567 <400> SEQUENCE: 567 000 <210> SEQ ID NO 568
<400> SEQUENCE: 568 000 <210> SEQ ID NO 569 <400>
SEQUENCE: 569 000 <210> SEQ ID NO 570 <400> SEQUENCE:
570 000 <210> SEQ ID NO 571 <400> SEQUENCE: 571 000
<210> SEQ ID NO 572 <400> SEQUENCE: 572 000 <210>
SEQ ID NO 573 <400> SEQUENCE: 573 000 <210> SEQ ID NO
574 <400> SEQUENCE: 574 000 <210> SEQ ID NO 575
<400> SEQUENCE: 575 000 <210> SEQ ID NO 576 <400>
SEQUENCE: 576 000 <210> SEQ ID NO 577 <400> SEQUENCE:
577 000 <210> SEQ ID NO 578 <400> SEQUENCE: 578 000
<210> SEQ ID NO 579 <400> SEQUENCE: 579 000 <210>
SEQ ID NO 580 <400> SEQUENCE: 580 000 <210> SEQ ID NO
581 <400> SEQUENCE: 581 000 <210> SEQ ID NO 582
<400> SEQUENCE: 582 000
<210> SEQ ID NO 583 <400> SEQUENCE: 583 000 <210>
SEQ ID NO 584 <400> SEQUENCE: 584 000 <210> SEQ ID NO
585 <400> SEQUENCE: 585 000 <210> SEQ ID NO 586
<400> SEQUENCE: 586 000 <210> SEQ ID NO 587 <400>
SEQUENCE: 587 000 <210> SEQ ID NO 588 <400> SEQUENCE:
588 000 <210> SEQ ID NO 589 <400> SEQUENCE: 589 000
<210> SEQ ID NO 590 <400> SEQUENCE: 590 000 <210>
SEQ ID NO 591 <400> SEQUENCE: 591 000 <210> SEQ ID NO
592 <400> SEQUENCE: 592 000 <210> SEQ ID NO 593
<400> SEQUENCE: 593 000 <210> SEQ ID NO 594 <400>
SEQUENCE: 594 000 <210> SEQ ID NO 595 <400> SEQUENCE:
595 000 <210> SEQ ID NO 596 <400> SEQUENCE: 596 000
<210> SEQ ID NO 597 <400> SEQUENCE: 597 000 <210>
SEQ ID NO 598 <400> SEQUENCE: 598 000 <210> SEQ ID NO
599 <400> SEQUENCE: 599 000 <210> SEQ ID NO 600
<400> SEQUENCE: 600 000 <210> SEQ ID NO 601 <400>
SEQUENCE: 601 000 <210> SEQ ID NO 602 <400> SEQUENCE:
602 000 <210> SEQ ID NO 603 <400> SEQUENCE: 603 000
<210> SEQ ID NO 604 <400> SEQUENCE: 604 000 <210>
SEQ ID NO 605 <400> SEQUENCE: 605 000 <210> SEQ ID NO
606 <400> SEQUENCE: 606 000 <210> SEQ ID NO 607
<400> SEQUENCE: 607 000 <210> SEQ ID NO 608 <400>
SEQUENCE: 608 000 <210> SEQ ID NO 609 <400> SEQUENCE:
609 000 <210> SEQ ID NO 610 <400> SEQUENCE: 610 000
<210> SEQ ID NO 611 <400> SEQUENCE: 611 000 <210>
SEQ ID NO 612 <400> SEQUENCE: 612 000 <210> SEQ ID NO
613 <400> SEQUENCE: 613 000 <210> SEQ ID NO 614
<400> SEQUENCE: 614 000 <210> SEQ ID NO 615 <400>
SEQUENCE: 615 000 <210> SEQ ID NO 616 <400> SEQUENCE:
616 000 <210> SEQ ID NO 617 <400> SEQUENCE: 617 000
<210> SEQ ID NO 618 <400> SEQUENCE: 618 000
<210> SEQ ID NO 619 <400> SEQUENCE: 619 000 <210>
SEQ ID NO 620 <400> SEQUENCE: 620 000 <210> SEQ ID NO
621 <400> SEQUENCE: 621 000 <210> SEQ ID NO 622
<400> SEQUENCE: 622 000 <210> SEQ ID NO 623 <400>
SEQUENCE: 623 000 <210> SEQ ID NO 624 <400> SEQUENCE:
624 000 <210> SEQ ID NO 625 <400> SEQUENCE: 625 000
<210> SEQ ID NO 626 <400> SEQUENCE: 626 000 <210>
SEQ ID NO 627 <400> SEQUENCE: 627 000 <210> SEQ ID NO
628 <400> SEQUENCE: 628 000 <210> SEQ ID NO 629
<400> SEQUENCE: 629 000 <210> SEQ ID NO 630 <400>
SEQUENCE: 630 000 <210> SEQ ID NO 631 <400> SEQUENCE:
631 000 <210> SEQ ID NO 632 <400> SEQUENCE: 632 000
<210> SEQ ID NO 633 <400> SEQUENCE: 633 000 <210>
SEQ ID NO 634 <400> SEQUENCE: 634 000 <210> SEQ ID NO
635 <400> SEQUENCE: 635 000 <210> SEQ ID NO 636
<400> SEQUENCE: 636 000 <210> SEQ ID NO 637 <400>
SEQUENCE: 637 000 <210> SEQ ID NO 638 <400> SEQUENCE:
638 000 <210> SEQ ID NO 639 <400> SEQUENCE: 639 000
<210> SEQ ID NO 640 <400> SEQUENCE: 640 000 <210>
SEQ ID NO 641 <400> SEQUENCE: 641 000 <210> SEQ ID NO
642 <400> SEQUENCE: 642 000 <210> SEQ ID NO 643
<400> SEQUENCE: 643 000 <210> SEQ ID NO 644 <400>
SEQUENCE: 644 000 <210> SEQ ID NO 645 <400> SEQUENCE:
645 000 <210> SEQ ID NO 646 <400> SEQUENCE: 646 000
<210> SEQ ID NO 647 <400> SEQUENCE: 647 000 <210>
SEQ ID NO 648 <400> SEQUENCE: 648 000 <210> SEQ ID NO
649 <400> SEQUENCE: 649 000 <210> SEQ ID NO 650
<400> SEQUENCE: 650 000 <210> SEQ ID NO 651 <400>
SEQUENCE: 651 000 <210> SEQ ID NO 652 <400> SEQUENCE:
652 000 <210> SEQ ID NO 653 <400> SEQUENCE: 653 000
<210> SEQ ID NO 654 <400> SEQUENCE: 654 000
<210> SEQ ID NO 655 <400> SEQUENCE: 655 000 <210>
SEQ ID NO 656 <400> SEQUENCE: 656 000 <210> SEQ ID NO
657 <400> SEQUENCE: 657 000 <210> SEQ ID NO 658
<400> SEQUENCE: 658 000 <210> SEQ ID NO 659 <400>
SEQUENCE: 659 000 <210> SEQ ID NO 660 <400> SEQUENCE:
660 000 <210> SEQ ID NO 661 <400> SEQUENCE: 661 000
<210> SEQ ID NO 662 <400> SEQUENCE: 662 000 <210>
SEQ ID NO 663 <400> SEQUENCE: 663 000 <210> SEQ ID NO
664 <400> SEQUENCE: 664 000 <210> SEQ ID NO 665
<400> SEQUENCE: 665 000 <210> SEQ ID NO 666 <400>
SEQUENCE: 666 000 <210> SEQ ID NO 667 <400> SEQUENCE:
667 000 <210> SEQ ID NO 668 <400> SEQUENCE: 668 000
<210> SEQ ID NO 669 <400> SEQUENCE: 669 000 <210>
SEQ ID NO 670 <400> SEQUENCE: 670 000 <210> SEQ ID NO
671 <400> SEQUENCE: 671 000 <210> SEQ ID NO 672
<400> SEQUENCE: 672 000 <210> SEQ ID NO 673 <400>
SEQUENCE: 673 000 <210> SEQ ID NO 674 <400> SEQUENCE:
674 000 <210> SEQ ID NO 675 <400> SEQUENCE: 675 000
<210> SEQ ID NO 676 <400> SEQUENCE: 676 000 <210>
SEQ ID NO 677 <400> SEQUENCE: 677 000 <210> SEQ ID NO
678 <400> SEQUENCE: 678 000 <210> SEQ ID NO 679
<400> SEQUENCE: 679 000 <210> SEQ ID NO 680 <400>
SEQUENCE: 680 000 <210> SEQ ID NO 681 <400> SEQUENCE:
681 000 <210> SEQ ID NO 682 <400> SEQUENCE: 682 000
<210> SEQ ID NO 683 <400> SEQUENCE: 683 000 <210>
SEQ ID NO 684 <400> SEQUENCE: 684 000 <210> SEQ ID NO
685 <400> SEQUENCE: 685 000 <210> SEQ ID NO 686
<400> SEQUENCE: 686 000 <210> SEQ ID NO 687 <400>
SEQUENCE: 687 000 <210> SEQ ID NO 688 <400> SEQUENCE:
688 000 <210> SEQ ID NO 689 <400> SEQUENCE: 689 000
<210> SEQ ID NO 690 <400> SEQUENCE: 690
000 <210> SEQ ID NO 691 <400> SEQUENCE: 691 000
<210> SEQ ID NO 692 <400> SEQUENCE: 692 000 <210>
SEQ ID NO 693 <400> SEQUENCE: 693 000 <210> SEQ ID NO
694 <400> SEQUENCE: 694 000 <210> SEQ ID NO 695
<400> SEQUENCE: 695 000 <210> SEQ ID NO 696 <400>
SEQUENCE: 696 000 <210> SEQ ID NO 697 <400> SEQUENCE:
697 000 <210> SEQ ID NO 698 <400> SEQUENCE: 698 000
<210> SEQ ID NO 699 <400> SEQUENCE: 699 000 <210>
SEQ ID NO 700 <400> SEQUENCE: 700 000 <210> SEQ ID NO
701 <400> SEQUENCE: 701 000 <210> SEQ ID NO 702
<400> SEQUENCE: 702 000 <210> SEQ ID NO 703 <400>
SEQUENCE: 703 000 <210> SEQ ID NO 704 <400> SEQUENCE:
704 000 <210> SEQ ID NO 705 <400> SEQUENCE: 705 000
<210> SEQ ID NO 706 <400> SEQUENCE: 706 000 <210>
SEQ ID NO 707 <400> SEQUENCE: 707 000 <210> SEQ ID NO
708 <400> SEQUENCE: 708 000 <210> SEQ ID NO 709
<400> SEQUENCE: 709 000 <210> SEQ ID NO 710 <400>
SEQUENCE: 710 000 <210> SEQ ID NO 711 <400> SEQUENCE:
711 000 <210> SEQ ID NO 712 <400> SEQUENCE: 712 000
<210> SEQ ID NO 713 <400> SEQUENCE: 713 000 <210>
SEQ ID NO 714 <400> SEQUENCE: 714 000 <210> SEQ ID NO
715 <400> SEQUENCE: 715 000 <210> SEQ ID NO 716
<400> SEQUENCE: 716 000 <210> SEQ ID NO 717 <400>
SEQUENCE: 717 000 <210> SEQ ID NO 718 <400> SEQUENCE:
718 000 <210> SEQ ID NO 719 <400> SEQUENCE: 719 000
<210> SEQ ID NO 720 <400> SEQUENCE: 720 000 <210>
SEQ ID NO 721 <400> SEQUENCE: 721 000 <210> SEQ ID NO
722 <400> SEQUENCE: 722 000 <210> SEQ ID NO 723
<400> SEQUENCE: 723 000 <210> SEQ ID NO 724 <400>
SEQUENCE: 724 000 <210> SEQ ID NO 725 <400> SEQUENCE:
725 000 <210> SEQ ID NO 726 <400> SEQUENCE: 726
000 <210> SEQ ID NO 727 <400> SEQUENCE: 727 000
<210> SEQ ID NO 728 <400> SEQUENCE: 728 000 <210>
SEQ ID NO 729 <400> SEQUENCE: 729 000 <210> SEQ ID NO
730 <400> SEQUENCE: 730 000 <210> SEQ ID NO 731
<400> SEQUENCE: 731 000 <210> SEQ ID NO 732 <400>
SEQUENCE: 732 000 <210> SEQ ID NO 733 <400> SEQUENCE:
733 000 <210> SEQ ID NO 734 <400> SEQUENCE: 734 000
<210> SEQ ID NO 735 <400> SEQUENCE: 735 000 <210>
SEQ ID NO 736 <400> SEQUENCE: 736 000 <210> SEQ ID NO
737 <400> SEQUENCE: 737 000 <210> SEQ ID NO 738
<400> SEQUENCE: 738 000 <210> SEQ ID NO 739 <400>
SEQUENCE: 739 000 <210> SEQ ID NO 740 <400> SEQUENCE:
740 000 <210> SEQ ID NO 741 <400> SEQUENCE: 741 000
<210> SEQ ID NO 742 <400> SEQUENCE: 742 000 <210>
SEQ ID NO 743 <400> SEQUENCE: 743 000 <210> SEQ ID NO
744 <400> SEQUENCE: 744 000 <210> SEQ ID NO 745
<400> SEQUENCE: 745 000 <210> SEQ ID NO 746 <400>
SEQUENCE: 746 000 <210> SEQ ID NO 747 <400> SEQUENCE:
747 000 <210> SEQ ID NO 748 <400> SEQUENCE: 748 000
<210> SEQ ID NO 749 <400> SEQUENCE: 749 000 <210>
SEQ ID NO 750 <400> SEQUENCE: 750 000 <210> SEQ ID NO
751 <400> SEQUENCE: 751 000 <210> SEQ ID NO 752
<400> SEQUENCE: 752 000 <210> SEQ ID NO 753 <400>
SEQUENCE: 753 000 <210> SEQ ID NO 754 <400> SEQUENCE:
754 000 <210> SEQ ID NO 755 <400> SEQUENCE: 755 000
<210> SEQ ID NO 756 <400> SEQUENCE: 756 000 <210>
SEQ ID NO 757 <400> SEQUENCE: 757 000 <210> SEQ ID NO
758 <400> SEQUENCE: 758 000 <210> SEQ ID NO 759
<400> SEQUENCE: 759 000 <210> SEQ ID NO 760 <400>
SEQUENCE: 760 000 <210> SEQ ID NO 761 <400> SEQUENCE:
761 000 <210> SEQ ID NO 762
<400> SEQUENCE: 762 000 <210> SEQ ID NO 763 <400>
SEQUENCE: 763 000 <210> SEQ ID NO 764 <400> SEQUENCE:
764 000 <210> SEQ ID NO 765 <400> SEQUENCE: 765 000
<210> SEQ ID NO 766 <400> SEQUENCE: 766 000 <210>
SEQ ID NO 767 <400> SEQUENCE: 767 000 <210> SEQ ID NO
768 <400> SEQUENCE: 768 000 <210> SEQ ID NO 769
<400> SEQUENCE: 769 000 <210> SEQ ID NO 770 <400>
SEQUENCE: 770 000 <210> SEQ ID NO 771 <400> SEQUENCE:
771 000 <210> SEQ ID NO 772 <400> SEQUENCE: 772 000
<210> SEQ ID NO 773 <400> SEQUENCE: 773 000 <210>
SEQ ID NO 774 <400> SEQUENCE: 774 000 <210> SEQ ID NO
775 <400> SEQUENCE: 775 000 <210> SEQ ID NO 776
<400> SEQUENCE: 776 000 <210> SEQ ID NO 777 <400>
SEQUENCE: 777 000 <210> SEQ ID NO 778 <400> SEQUENCE:
778 000 <210> SEQ ID NO 779 <400> SEQUENCE: 779 000
<210> SEQ ID NO 780 <400> SEQUENCE: 780 000 <210>
SEQ ID NO 781 <400> SEQUENCE: 781 000 <210> SEQ ID NO
782 <400> SEQUENCE: 782 000 <210> SEQ ID NO 783
<400> SEQUENCE: 783 000 <210> SEQ ID NO 784 <400>
SEQUENCE: 784 000 <210> SEQ ID NO 785 <400> SEQUENCE:
785 000 <210> SEQ ID NO 786 <400> SEQUENCE: 786 000
<210> SEQ ID NO 787 <400> SEQUENCE: 787 000 <210>
SEQ ID NO 788 <400> SEQUENCE: 788 000 <210> SEQ ID NO
789 <400> SEQUENCE: 789 000 <210> SEQ ID NO 790
<400> SEQUENCE: 790 000 <210> SEQ ID NO 791 <400>
SEQUENCE: 791 000 <210> SEQ ID NO 792 <400> SEQUENCE:
792 000 <210> SEQ ID NO 793 <400> SEQUENCE: 793 000
<210> SEQ ID NO 794 <400> SEQUENCE: 794 000 <210>
SEQ ID NO 795 <400> SEQUENCE: 795 000 <210> SEQ ID NO
796 <400> SEQUENCE: 796 000 <210> SEQ ID NO 797
<400> SEQUENCE: 797 000 <210> SEQ ID NO 798
<400> SEQUENCE: 798 000 <210> SEQ ID NO 799 <400>
SEQUENCE: 799 000 <210> SEQ ID NO 800 <400> SEQUENCE:
800 000 <210> SEQ ID NO 801 <400> SEQUENCE: 801 000
<210> SEQ ID NO 802 <400> SEQUENCE: 802 000 <210>
SEQ ID NO 803 <400> SEQUENCE: 803 000 <210> SEQ ID NO
804 <400> SEQUENCE: 804 000 <210> SEQ ID NO 805
<400> SEQUENCE: 805 000 <210> SEQ ID NO 806 <400>
SEQUENCE: 806 000 <210> SEQ ID NO 807 <400> SEQUENCE:
807 000 <210> SEQ ID NO 808 <400> SEQUENCE: 808 000
<210> SEQ ID NO 809 <400> SEQUENCE: 809 000 <210>
SEQ ID NO 810 <400> SEQUENCE: 810 000 <210> SEQ ID NO
811 <400> SEQUENCE: 811 000 <210> SEQ ID NO 812
<400> SEQUENCE: 812 000 <210> SEQ ID NO 813 <400>
SEQUENCE: 813 000 <210> SEQ ID NO 814 <400> SEQUENCE:
814 000 <210> SEQ ID NO 815 <400> SEQUENCE: 815 000
<210> SEQ ID NO 816 <400> SEQUENCE: 816 000 <210>
SEQ ID NO 817 <400> SEQUENCE: 817 000 <210> SEQ ID NO
818 <400> SEQUENCE: 818 000 <210> SEQ ID NO 819
<400> SEQUENCE: 819 000 <210> SEQ ID NO 820 <400>
SEQUENCE: 820 000 <210> SEQ ID NO 821 <400> SEQUENCE:
821 000 <210> SEQ ID NO 822 <400> SEQUENCE: 822 000
<210> SEQ ID NO 823 <400> SEQUENCE: 823 000 <210>
SEQ ID NO 824 <400> SEQUENCE: 824 000 <210> SEQ ID NO
825 <400> SEQUENCE: 825 000 <210> SEQ ID NO 826
<400> SEQUENCE: 826 000 <210> SEQ ID NO 827 <400>
SEQUENCE: 827 000 <210> SEQ ID NO 828 <400> SEQUENCE:
828 000 <210> SEQ ID NO 829 <400> SEQUENCE: 829 000
<210> SEQ ID NO 830 <400> SEQUENCE: 830 000 <210>
SEQ ID NO 831 <400> SEQUENCE: 831 000 <210> SEQ ID NO
832 <400> SEQUENCE: 832 000 <210> SEQ ID NO 833
<400> SEQUENCE: 833 000
<210> SEQ ID NO 834 <400> SEQUENCE: 834 000 <210>
SEQ ID NO 835 <400> SEQUENCE: 835 000 <210> SEQ ID NO
836 <400> SEQUENCE: 836 000 <210> SEQ ID NO 837
<400> SEQUENCE: 837 000 <210> SEQ ID NO 838 <400>
SEQUENCE: 838 000 <210> SEQ ID NO 839 <400> SEQUENCE:
839 000 <210> SEQ ID NO 840 <400> SEQUENCE: 840 000
<210> SEQ ID NO 841 <400> SEQUENCE: 841 000 <210>
SEQ ID NO 842 <400> SEQUENCE: 842 000 <210> SEQ ID NO
843 <400> SEQUENCE: 843 000 <210> SEQ ID NO 844
<400> SEQUENCE: 844 000 <210> SEQ ID NO 845 <400>
SEQUENCE: 845 000 <210> SEQ ID NO 846 <400> SEQUENCE:
846 000 <210> SEQ ID NO 847 <400> SEQUENCE: 847 000
<210> SEQ ID NO 848 <400> SEQUENCE: 848 000 <210>
SEQ ID NO 849 <400> SEQUENCE: 849 000 <210> SEQ ID NO
850 <400> SEQUENCE: 850 000 <210> SEQ ID NO 851
<400> SEQUENCE: 851 000 <210> SEQ ID NO 852 <400>
SEQUENCE: 852 000 <210> SEQ ID NO 853 <400> SEQUENCE:
853 000 <210> SEQ ID NO 854 <400> SEQUENCE: 854 000
<210> SEQ ID NO 855 <400> SEQUENCE: 855 000 <210>
SEQ ID NO 856 <400> SEQUENCE: 856 000 <210> SEQ ID NO
857 <400> SEQUENCE: 857 000 <210> SEQ ID NO 858
<400> SEQUENCE: 858 000 <210> SEQ ID NO 859 <400>
SEQUENCE: 859 000 <210> SEQ ID NO 860 <400> SEQUENCE:
860 000 <210> SEQ ID NO 861 <400> SEQUENCE: 861 000
<210> SEQ ID NO 862 <400> SEQUENCE: 862 000 <210>
SEQ ID NO 863 <400> SEQUENCE: 863 000 <210> SEQ ID NO
864 <400> SEQUENCE: 864 000 <210> SEQ ID NO 865
<400> SEQUENCE: 865 000 <210> SEQ ID NO 866 <400>
SEQUENCE: 866 000 <210> SEQ ID NO 867 <400> SEQUENCE:
867 000 <210> SEQ ID NO 868 <400> SEQUENCE: 868 000
<210> SEQ ID NO 869 <400> SEQUENCE: 869 000
<210> SEQ ID NO 870 <400> SEQUENCE: 870 000 <210>
SEQ ID NO 871 <400> SEQUENCE: 871 000 <210> SEQ ID NO
872 <400> SEQUENCE: 872 000 <210> SEQ ID NO 873
<400> SEQUENCE: 873 000 <210> SEQ ID NO 874 <400>
SEQUENCE: 874 000 <210> SEQ ID NO 875 <400> SEQUENCE:
875 000 <210> SEQ ID NO 876 <400> SEQUENCE: 876 000
<210> SEQ ID NO 877 <400> SEQUENCE: 877 000 <210>
SEQ ID NO 878 <400> SEQUENCE: 878 000 <210> SEQ ID NO
879 <400> SEQUENCE: 879 000 <210> SEQ ID NO 880
<400> SEQUENCE: 880 000 <210> SEQ ID NO 881 <400>
SEQUENCE: 881 000 <210> SEQ ID NO 882 <400> SEQUENCE:
882 000 <210> SEQ ID NO 883 <400> SEQUENCE: 883 000
<210> SEQ ID NO 884 <400> SEQUENCE: 884 000 <210>
SEQ ID NO 885 <400> SEQUENCE: 885 000 <210> SEQ ID NO
886 <400> SEQUENCE: 886 000 <210> SEQ ID NO 887
<400> SEQUENCE: 887 000 <210> SEQ ID NO 888 <400>
SEQUENCE: 888 000 <210> SEQ ID NO 889 <400> SEQUENCE:
889 000 <210> SEQ ID NO 890 <400> SEQUENCE: 890 000
<210> SEQ ID NO 891 <400> SEQUENCE: 891 000 <210>
SEQ ID NO 892 <400> SEQUENCE: 892 000 <210> SEQ ID NO
893 <400> SEQUENCE: 893 000 <210> SEQ ID NO 894
<400> SEQUENCE: 894 000 <210> SEQ ID NO 895 <400>
SEQUENCE: 895 000 <210> SEQ ID NO 896 <400> SEQUENCE:
896 000 <210> SEQ ID NO 897 <400> SEQUENCE: 897 000
<210> SEQ ID NO 898 <400> SEQUENCE: 898 000 <210>
SEQ ID NO 899 <400> SEQUENCE: 899 000 <210> SEQ ID NO
900 <400> SEQUENCE: 900 000 <210> SEQ ID NO 901
<400> SEQUENCE: 901 000 <210> SEQ ID NO 902 <400>
SEQUENCE: 902 000 <210> SEQ ID NO 903 <400> SEQUENCE:
903 000 <210> SEQ ID NO 904 <400> SEQUENCE: 904 000
<210> SEQ ID NO 905 <400> SEQUENCE: 905 000
<210> SEQ ID NO 906 <400> SEQUENCE: 906 000 <210>
SEQ ID NO 907 <400> SEQUENCE: 907 000 <210> SEQ ID NO
908 <400> SEQUENCE: 908 000 <210> SEQ ID NO 909
<400> SEQUENCE: 909 000 <210> SEQ ID NO 910 <400>
SEQUENCE: 910 000 <210> SEQ ID NO 911 <400> SEQUENCE:
911 000 <210> SEQ ID NO 912 <400> SEQUENCE: 912 000
<210> SEQ ID NO 913 <400> SEQUENCE: 913 000 <210>
SEQ ID NO 914 <400> SEQUENCE: 914 000 <210> SEQ ID NO
915 <400> SEQUENCE: 915 000 <210> SEQ ID NO 916
<400> SEQUENCE: 916 000 <210> SEQ ID NO 917 <400>
SEQUENCE: 917 000 <210> SEQ ID NO 918 <400> SEQUENCE:
918 000 <210> SEQ ID NO 919 <400> SEQUENCE: 919 000
<210> SEQ ID NO 920 <400> SEQUENCE: 920 000 <210>
SEQ ID NO 921 <400> SEQUENCE: 921 000 <210> SEQ ID NO
922 <400> SEQUENCE: 922 000 <210> SEQ ID NO 923
<400> SEQUENCE: 923 000 <210> SEQ ID NO 924 <400>
SEQUENCE: 924 000 <210> SEQ ID NO 925 <400> SEQUENCE:
925 000 <210> SEQ ID NO 926 <400> SEQUENCE: 926 000
<210> SEQ ID NO 927 <400> SEQUENCE: 927 000 <210>
SEQ ID NO 928 <400> SEQUENCE: 928 000 <210> SEQ ID NO
929 <400> SEQUENCE: 929 000 <210> SEQ ID NO 930
<400> SEQUENCE: 930 000 <210> SEQ ID NO 931 <400>
SEQUENCE: 931 000 <210> SEQ ID NO 932 <400> SEQUENCE:
932 000 <210> SEQ ID NO 933 <400> SEQUENCE: 933 000
<210> SEQ ID NO 934 <400> SEQUENCE: 934 000 <210>
SEQ ID NO 935 <400> SEQUENCE: 935 000 <210> SEQ ID NO
936 <400> SEQUENCE: 936 000 <210> SEQ ID NO 937
<400> SEQUENCE: 937 000 <210> SEQ ID NO 938 <400>
SEQUENCE: 938 000 <210> SEQ ID NO 939 <400> SEQUENCE:
939 000 <210> SEQ ID NO 940 <400> SEQUENCE: 940 000
<210> SEQ ID NO 941 <400> SEQUENCE: 941
000 <210> SEQ ID NO 942 <400> SEQUENCE: 942 000
<210> SEQ ID NO 943 <400> SEQUENCE: 943 000 <210>
SEQ ID NO 944 <400> SEQUENCE: 944 000 <210> SEQ ID NO
945 <400> SEQUENCE: 945 000 <210> SEQ ID NO 946
<400> SEQUENCE: 946 000 <210> SEQ ID NO 947 <400>
SEQUENCE: 947 000 <210> SEQ ID NO 948 <400> SEQUENCE:
948 000 <210> SEQ ID NO 949 <400> SEQUENCE: 949 000
<210> SEQ ID NO 950 <400> SEQUENCE: 950 000 <210>
SEQ ID NO 951 <400> SEQUENCE: 951 000 <210> SEQ ID NO
952 <400> SEQUENCE: 952 000 <210> SEQ ID NO 953
<400> SEQUENCE: 953 000 <210> SEQ ID NO 954 <400>
SEQUENCE: 954 000 <210> SEQ ID NO 955 <400> SEQUENCE:
955 000 <210> SEQ ID NO 956 <400> SEQUENCE: 956 000
<210> SEQ ID NO 957 <400> SEQUENCE: 957 000 <210>
SEQ ID NO 958 <400> SEQUENCE: 958 000 <210> SEQ ID NO
959 <400> SEQUENCE: 959 000 <210> SEQ ID NO 960
<400> SEQUENCE: 960 000 <210> SEQ ID NO 961 <400>
SEQUENCE: 961 000 <210> SEQ ID NO 962 <400> SEQUENCE:
962 000 <210> SEQ ID NO 963 <400> SEQUENCE: 963 000
<210> SEQ ID NO 964 <400> SEQUENCE: 964 000 <210>
SEQ ID NO 965 <400> SEQUENCE: 965 000 <210> SEQ ID NO
966 <400> SEQUENCE: 966 000 <210> SEQ ID NO 967
<400> SEQUENCE: 967 000 <210> SEQ ID NO 968 <400>
SEQUENCE: 968 000 <210> SEQ ID NO 969 <400> SEQUENCE:
969 000 <210> SEQ ID NO 970 <400> SEQUENCE: 970 000
<210> SEQ ID NO 971 <400> SEQUENCE: 971 000 <210>
SEQ ID NO 972 <400> SEQUENCE: 972 000 <210> SEQ ID NO
973 <400> SEQUENCE: 973 000 <210> SEQ ID NO 974
<400> SEQUENCE: 974 000 <210> SEQ ID NO 975 <400>
SEQUENCE: 975 000 <210> SEQ ID NO 976 <400> SEQUENCE:
976 000 <210> SEQ ID NO 977 <400> SEQUENCE: 977
000 <210> SEQ ID NO 978 <400> SEQUENCE: 978 000
<210> SEQ ID NO 979 <400> SEQUENCE: 979 000 <210>
SEQ ID NO 980 <400> SEQUENCE: 980 000 <210> SEQ ID NO
981 <400> SEQUENCE: 981 000 <210> SEQ ID NO 982
<400> SEQUENCE: 982 000 <210> SEQ ID NO 983 <400>
SEQUENCE: 983 000 <210> SEQ ID NO 984 <400> SEQUENCE:
984 000 <210> SEQ ID NO 985 <400> SEQUENCE: 985 000
<210> SEQ ID NO 986 <400> SEQUENCE: 986 000 <210>
SEQ ID NO 987 <400> SEQUENCE: 987 000 <210> SEQ ID NO
988 <400> SEQUENCE: 988 000 <210> SEQ ID NO 989
<400> SEQUENCE: 989 000 <210> SEQ ID NO 990 <400>
SEQUENCE: 990 000 <210> SEQ ID NO 991 <400> SEQUENCE:
991 000 <210> SEQ ID NO 992 <400> SEQUENCE: 992 000
<210> SEQ ID NO 993 <400> SEQUENCE: 993 000 <210>
SEQ ID NO 994 <400> SEQUENCE: 994 000 <210> SEQ ID NO
995 <400> SEQUENCE: 995 000 <210> SEQ ID NO 996
<400> SEQUENCE: 996 000 <210> SEQ ID NO 997 <400>
SEQUENCE: 997 000 <210> SEQ ID NO 998 <400> SEQUENCE:
998 000 <210> SEQ ID NO 999 <400> SEQUENCE: 999 000
<210> SEQ ID NO 1000 <211> LENGTH: 20 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 1000 Met Gly Phe Tyr Pro
Cys Trp Thr Ala Gln Leu Gly Glu Leu Cys Asp 1 5 10 15 Leu Ser Val
Asp 20 <210> SEQ ID NO 1001 <211> LENGTH: 19
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 1001
Gly Phe Tyr Pro Cys Trp Thr Ala Gln Leu Gly Glu Leu Cys Asp Leu 1 5
10 15 Ser Val Asp <210> SEQ ID NO 1002 <211> LENGTH: 18
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 1002
Phe Tyr Pro Cys Trp Thr Ala Gln Leu Gly Glu Leu Cys Asp Leu Ser 1 5
10 15 Val Asp <210> SEQ ID NO 1003 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 1003
Tyr Pro Cys Trp Thr Ala Gln Leu Gly Glu Leu Cys Asp Leu Ser Val 1 5
10 15 Asp <210> SEQ ID NO 1004 <211> LENGTH: 19
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 1004
Met Gly Phe Tyr Pro Cys Trp Thr Ala Gln Leu Gly Glu Leu Cys Asp 1 5
10 15 Leu Ser Val <210> SEQ ID NO 1005 <211> LENGTH: 18
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 1005 Met Gly Phe Tyr Pro Cys Trp Thr
Ala Gln Leu Gly Glu Leu Cys Asp 1 5 10 15 Leu Ser <210> SEQ
ID NO 1006 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 1006 Met Gly Phe Tyr Pro Cys Trp Thr
Ala Gln Leu Gly Glu Leu Cys Asp 1 5 10 15 Leu <210> SEQ ID NO
1007 <211> LENGTH: 18 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 1007 Gly Phe Tyr Pro Cys Trp Thr Ala
Gln Leu Gly Glu Leu Cys Asp Leu 1 5 10 15 Ser Val <210> SEQ
ID NO 1008 <211> LENGTH: 15 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 1008 Phe Tyr Pro Cys Trp Thr Ala Gln
Leu Gly Glu Leu Cys Asp Leu 1 5 10 15 <210> SEQ ID NO 1009
<400> SEQUENCE: 1009 000 <210> SEQ ID NO 1010
<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 1010 Lys Tyr Cys Gly Phe Ala Gln Leu Gly Glu
Leu Cys Val Leu 1 5 10 <210> SEQ ID NO 1011 <211>
LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 1011 Gly Lys Tyr Cys Gly Phe Ala Gln Leu Gly Glu Leu Cys
Val Leu 1 5 10 15 <210> SEQ ID NO 1012 <211> LENGTH: 16
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 1012
Gly Gly Lys Tyr Cys Gly Phe Ala Gln Leu Gly Glu Leu Cys Val Leu 1 5
10 15 <210> SEQ ID NO 1013 <211> LENGTH: 17 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: Description of Artificial
Sequence: Synthetic peptide <400> SEQUENCE: 1013 Gly Gly Gly
Lys Tyr Cys Gly Phe Ala Gln Leu Gly Glu Leu Cys Val 1 5 10 15 Leu
<210> SEQ ID NO 1014 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 1014 Lys Tyr Cys Gly Phe
Ala Gln Leu Gly Glu Leu Cys Val Leu Gly 1 5 10 15 <210> SEQ
ID NO 1015 <211> LENGTH: 16 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 1015 Lys Tyr Cys Gly Phe Ala Gln Leu
Gly Glu Leu Cys Val Leu Gly Gly 1 5 10 15 <210> SEQ ID NO
1016 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 1016 Lys Tyr Cys Gly Phe Ala Gln Leu
Gly Glu Leu Cys Val Leu Gly Gly 1 5 10 15 Gly <210> SEQ ID NO
1017 <211> LENGTH: 16 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 1017 Gly Lys Tyr Cys Gly Phe Ala Gln
Leu Gly Glu Leu Cys Val Leu Gly 1 5 10 15 <210> SEQ ID NO
1018 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 1018 Gly Gly Lys Tyr Cys Gly Phe Ala
Gln Leu Gly Glu Leu Cys Val Leu 1 5 10 15 Gly <210> SEQ ID NO
1019 <400> SEQUENCE: 1019 000 <210> SEQ ID NO 1020
<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 1020 Tyr Trp Cys Trp Met Ala Gln Val Gly Glu
Leu Cys Asp Leu 1 5 10 <210> SEQ ID NO 1021 <211>
LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 1021 Tyr His Cys Trp Met Ala Gln Val Gly Glu Leu Cys Asp
Leu 1 5 10 <210> SEQ ID NO 1022 <211> LENGTH: 14
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 1022 Tyr His Cys Trp Met Gly Gln Val
Gly Glu Leu Cys Asp Leu 1 5 10 <210> SEQ ID NO 1023
<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 1023 Tyr His Cys Trp Met Gly Gln Met Gly Glu
Leu Cys Asp Leu 1 5 10 <210> SEQ ID NO 1024 <211>
LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 1024 Tyr His Cys Trp Met Gly Gln Met Gly Glu Leu Cys Glu
Leu 1 5 10 <210> SEQ ID NO 1025 <211> LENGTH: 14
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 1025
Tyr His Cys Trp Met Gly Gln Met Gly Glu Leu Cys Glu Met 1 5 10
<210> SEQ ID NO 1026 <400> SEQUENCE: 1026 000
<210> SEQ ID NO 1027 <400> SEQUENCE: 1027 000
<210> SEQ ID NO 1028 <400> SEQUENCE: 1028 000
<210> SEQ ID NO 1029 <400> SEQUENCE: 1029 000
<210> SEQ ID NO 1030 <211> LENGTH: 20 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 1030 Tyr Pro Cys Trp Leu
Ala Arg Val Gly Glu Leu Cys Asp Leu Asp Ser 1 5 10 15 Gly Asp Val
His 20 <210> SEQ ID NO 1031 <211> LENGTH: 20
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 1031
Ala Pro Cys Trp Leu Ala Arg Val Gly Glu Leu Cys Asp Leu Asp Ser 1 5
10 15 Gly Asp Val His 20 <210> SEQ ID NO 1032 <211>
LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 1032 Ala Pro Cys Ala Leu Ala Arg Val Gly Glu Leu Cys Asp
Leu Asp Ser 1 5 10 15 Gly Asp Val His 20 <210> SEQ ID NO 1033
<211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 1033 Ala Pro Cys Ala Leu Ala Ala Val Gly Glu
Leu Cys Asp Leu Asp Ser 1 5 10 15 Gly Asp Val His 20 <210>
SEQ ID NO 1034 <211> LENGTH: 20 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 1034 Ala Pro Cys Ala Leu
Ala Ala Val Gly Ala Leu Cys Asp Leu Asp Ser 1 5 10 15 Gly Asp Val
His 20 <210> SEQ ID NO 1035 <211> LENGTH: 20
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide <400> SEQUENCE: 1035
Ala Pro Cys Ala Leu Ala Ala Val Gly Ala Leu Cys Asp Leu Ala Ser 1 5
10 15 Gly Asp Val His 20 <210> SEQ ID NO 1036 <211>
LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
Description of Artificial Sequence: Synthetic peptide <400>
SEQUENCE: 1036 Ala Pro Cys Ala Leu Ala Ala Val Gly Ala Leu Cys Asp
Leu Ala Ala 1 5 10 15 Gly Asp Val His 20 <210> SEQ ID NO 1037
<211> LENGTH: 22 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 1037 Arg Asp Gln Tyr Tyr Pro Cys Trp Met Ala
Gln Leu Gly Glu Leu Cys 1 5 10 15 Asp Leu Asp Glu Val Phe 20
<210> SEQ ID NO 1038 <211> LENGTH: 22 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 1038 Arg Asp Gln Tyr Tyr
Pro Cys Tyr Met Ala Gln Leu Gly Glu Leu Cys 1 5 10 15 Asp Leu Glu
Glu Val Phe 20 <210> SEQ ID NO 1039 <211> LENGTH: 4
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of
Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 1039 Gly Gly Gly Ser 1 <210> SEQ ID NO
1040 <211> LENGTH: 5 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
peptide <400> SEQUENCE: 1040 Gly Gly Gly Gly Ser 1 5
<210> SEQ ID NO 1041 <211> LENGTH: 4 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (1)..(4) <223> OTHER
INFORMATION: This sequence may encompass 1-4 residues <400>
SEQUENCE: 1041 Gly Gly Gly Gly 1
* * * * *